US9695230B2 - Broadly neutralizing HIV-1 VRC07 antibodies that bind to the CD4-binding site of the envelope protein - Google Patents

Broadly neutralizing HIV-1 VRC07 antibodies that bind to the CD4-binding site of the envelope protein Download PDF

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US9695230B2
US9695230B2 US14/363,740 US201214363740A US9695230B2 US 9695230 B2 US9695230 B2 US 9695230B2 US 201214363740 A US201214363740 A US 201214363740A US 9695230 B2 US9695230 B2 US 9695230B2
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amino acid
antibody
variable domain
chain variable
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US20140322163A1 (en
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Peter D. Kwong
Gary J. Nabel
Rebecca S. Rudicell
John Mascola
Mark Connors
Ivelin Georgiev
Jiang Zhu
Young Do Kwon
Tongqing Zhou
YongPing Yang
Baoshan Zhang
Gwo-Yu Chuang
Xueling Wu
Zhi-Yong Yang
Wei Shi
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US Department of Health and Human Services
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Assigned to THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES reassignment THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NABEL, GARY J., KWONG, PETER D., CONNORS, MARK, ZHU, JIANG, YANG, YONGPING, ZHOU, TONGQING, YANG, ZHI-YONG, CHUANG, Gwo-yu, ZHANG, BAOSHAN, GEORGIEV, Ivelin, KWON, YOUNG DO, MASCOLA, JOHN, RUDICELL, REBECCA S., SHI, WEI, WU, XUELING
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—RNA viruses
    • C07K16/112—Retroviridae (F), e.g. leukemia viruses
    • C07K16/114—Lentivirus (G), e.g. human immunodeficiency virus [HIV], feline immunodeficiency virus [FIV] or simian immunodeficiency virus [SIV]
    • C07K16/1145—Env proteins, e.g. gp41, gp110/120, gp160, V3, principal neutralising domain [PND] or CD4-binding site
    • C07K16/1063—
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G01N33/56988—HIV or HTLV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567—Framework region [FR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/72—Increased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • Monoclonal neutralizing antibodies are disclosed that bind to HIV-1 gp120, as well as their identification and use.
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immunodeficiency Syndrome
  • HIV-1 neutralizing mAb can bind to a site on gp120 that is required for viral attachment to its primary cellular receptor, CD4.
  • mAb b12 was derived from a phage display library, a process which makes it impossible to know if the antibody was naturally present in an infected person, or was the result of a laboratory combination of antibody heavy and light chains. b12 can neutralize about 75% of Glade B strains of HIV-1 (those most common in North America), but it neutralizes less than 50% of other strains of HIV-1 found worldwide. Therefore, there is a need to develop additional neutralizing antibodies for HIV-1.
  • VRC07 monoclonal antibody which specifically binds to the CD4 binding site of the gp120 protein of HIV, and is neutralizing VRC07 is a VRC01-like monoclonal antibody, and includes a novel heavy chain (“VRC07 heavy chain”). This heavy chain can cross-complement with the light chain of the VRC01 monoclonal antibody.
  • VRC07 heavy chain is a clonal variant of the VRC01 heavy chain.
  • An antibody including the VRC07 heavy chain cross complemented with the VRC01 light chain has increased binding affinity for gp120 and does not have significantly increased self-reactivity compared to VRC01.
  • variants of the VRC07 heavy chain and the VRC01 light chain and cross-complemented monoclonal antibodies including such variants that have increased binding affinity for gp120 and are not self-reactive, or have only low self reactivity, for example, compared to VRC01.
  • the disclosed variants of the VRC07 heavy chain and the VRC01 light chain include framework region amino acid substitutions (compared to VRC07 heavy chain or VRC01 light chain), but only include up to two amino acid substitutions in the CDRs (compared to VRC07 heavy chain or VRC01 light chain).
  • the disclosed antibodies further are not immunogenic, or have low immunogenicity.
  • isolated monoclonal neutralizing antibodies that specifically bind HIV-1 gp120 are provided herein.
  • the binding and/or neutralization ability of these antibodies has been optimized.
  • compositions including these antibodies that specifically bind gp120, nucleic acids encoding these antibodies, expression vectors comprising the nucleic acids, and isolated host cells that express the nucleic acids can be fully human.
  • the antibodies include a heavy chain variable domain and a light chain variable domain.
  • the isolated monoclonal antibody includes a heavy chain variable domain comprising amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40, wherein the antibody specifically binds gp120 of HIV-1, wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain comprising (a) amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40, wherein X 2 is G; or (b) amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40, wherein X 2 is H, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the antibody comprises SEQ ID NO: 40. In some embodiments, the heavy chain variable domain of the antibody comprises one of SEQ ID NO: 32, SEQ ID NO: 258, SEQ ID NO: 259, or SEQ ID NO: 260.
  • the light chain variable domain of the antibody comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238.
  • the isolated monoclonal antibody includes a light chain variable domain comprising (a) amino 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is D (VRC01 light chain CDRs with F97D), (b) amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is K (VRC01 light chain CDRs with F97K), (c) amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is S (VRC01 light chain CDRs with F97S); or (d) amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR
  • the light chain variable domain of the antibody comprises SEQ ID NO: 238. In some embodiments, the light chain variable domain of the antibody comprises one of SEQ ID NO: 9, SEQ ID NO: 219, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 222, SEQ ID NO: 223, SEQ ID NO: 224, SEQ ID NO: 225, SEQ ID NO: 226, SEQ ID NO: 227, SEQ ID NO: 228, SEQ ID NO: 229, SEQ ID NO: 230, SEQ ID NO: 231, SEQ ID NO: 232, SEQ ID NO: 233, SEQ ID NO: 234, SEQ ID NO: 235, SEQ ID NO: 236, or SEQ ID NO: 237.
  • a disclosed monoclonal antibody that specifically binds to gp120 includes a light chain including a disclosed light chain variable domain cross-complemented with a heavy chain including a disclosed heavy chain variable domain.
  • the antibodies and compositions disclosed herein can be used for a variety of purposes, such as for detecting an HIV-1 infection or diagnosing AIDS in a subject. These methods can include contacting a sample from the subject diagnosed with HIV-1 or AIDS with a human monoclonal antibody that specifically binds gp120, and detecting binding of the antibody to the sample. An increase in binding of the antibody to the sample relative to binding of the antibody to a control sample confirms that the subject has an HIV-1 infection and/or AIDS.
  • the methods further comprise contacting a second antibody that specifically binds gp120 with the sample, and detecting binding of the second antibody. In some non-limiting examples an increase in binding of the antibody to the sample relative to a control sample detects HIV-1 in the subject.
  • the antibody specifically binds soluble gp120 in the sample.
  • the methods further comprise contacting a second antibody that specifically recognizes the gp120 specific antibody with the sample and detecting binding of the second antibody.
  • a method for treating a subject with or at risk of an HIV infection, such as, but not limited to, an HIV seropositive subject or a subject with AIDS, or a person who has been exposed to potential HIV infection but not yet seroconverted.
  • the methods include administering a therapeutically effective amount of one or more of the monoclonal antibodies, antigen binding fragment thereof, or nucleic acid encoding antibody or antigen binding fragment, disclosed herein.
  • FIGS. 1A and 1B are a set of dot plots illustrating results of isolation of individual memory B cells producing anti-gp120 antibodies by cell sorting.
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • FIGS. 1A and 1B are a set of dot plots illustrating results of isolation of individual memory B cells producing anti-gp120 antibodies by cell sorting.
  • PBMC peripheral blood mononuclear cells
  • FIG. 2 is a protein sequence alignment showing the alignment of the heavy chain sequences of the VRC01 (SEQ ID NO: 5), VRC02 (SEQ ID NO: 197), VRC07 (SEQ ID NO: 2), VRC07b (SEQ ID NO: 3), VRC07c (SEQ ID NO: 4) and NIH4546 (SEQ ID NO: 196) monoclonal antibodies and the IGHV1-2*02 germline sequence (SEQ ID NO: 195).
  • the framework (FR) and complementarity determining region (CDR) positions are shown.
  • FIGS. 3A-3B are a protein and nucleotide sequence alignment showing the alignment of the heavy chain protein sequences of the VRC01 (SEQ ID NO: 5), VRC02 (SEQ ID NO: 197), VRC07 (SEQ ID NO: 2), VRC07b (SEQ ID NO: 3), VRC07c (SEQ ID NO: 4) and NIH4546 (SEQ ID NO: 196) heavy chain variable domains and the corresponding nucleotide sequence encoding the VRC07 heavy chain variable domain (SEQ ID NO: 10) as well as the nucleotide residues that differ from the VRC07 nucleotide sequence.
  • FIG. 4 shows the alignment of the nucleotide sequences encoding the heavy chains of the VRC01 (SEQ ID NO: 13), VRC02 (SEQ ID NO: 197), VRC07 (SEQ ID NO: 10), VRC07b (SEQ ID NO: 11), VRC07c (SEQ ID NO: 12) and NIH4546 (SEQ ID NO: 196) monoclonal antibodies.
  • FIG. 5 is a protein sequence alignment showing the alignment of the light chain variable domain sequences of the VRC01 (SEQ ID NO: 9), VRC07b (SEQ ID NO: 7) and VRC07c (SEQ ID NO: 8) monoclonal antibodies.
  • the IMGT CDR1, CDR2 and CDR3 sequences of each light chain sequence are underlined.
  • FIG. 6 is a table showing the results of antibody neutralization assays performed using the VRC01, VRC03, VRC-PG04 and VRC07 monoclonal antibodies.
  • the VRC07 antibody included the VRC07 heavy chain variable domain and the VRC01 light chain variable domain.
  • Neutralization was measured using HIV-1 Env-pseudoviruses (expressing HIV Env from the indicated HIV isotypes) to infect TZM-bl cells as described previously (see, e.g., PCT Pub. WO2011/038290) and luciferase assay was used as the output indicator.
  • the virus input was set at a multiplicity of infection of approximately 0.01, which generally results in 100,000 to 400,000 relative light units (RLU) in a luciferase assay (Bright Glo, Promega, Madison, Wis.).
  • RLU relative light units
  • the antibody concentrations were defined at the point of incubation with virus supernatant. Neutralization curves were fit by nonlinear regression using a 5-parameter hill slope equation.
  • the 50% and 80% inhibitory concentrations (IC50 and IC80) are listed in the table and were reported as the antibody concentrations required to inhibit infection by 50% and 80% respectively.
  • FIGS. 7A-D are a set of tables showing the results of antibody neutralization assays performed using the VRC01, VRC03, VRC-PG04, VRC-CH31, 4E10 and VRC07 monoclonal antibodies.
  • the VRC07 antibody included the VRC07 heavy chain variable domain (SEQ ID NO: 2) and the VRC01 light chain variable domain (SEQ ID NO: 9). Neutralization was measured as described in Example 2.
  • FIGS. 8A-8F show sequence alignments and tables concerning the VRC07 heavy chain variable domain and the VRC01 light chain variable domain.
  • FIGS. 8A and 8B show protein sequence alignments of the heavy chain variable domain sequences of the VRC01 (SEQ ID NO: 5), VRC02 (SEQ ID NO: 197), VRC07 (SEQ ID NO: 2), VRC07b (SEQ ID NO: 3), VRC07c (SEQ ID NO: 4) and NIH4546 (SEQ ID NO: 196) monoclonal antibodies.
  • the FR and CDR positions are shown using the IMGT ( FIG. 8B ) and Kabat ( FIG. 8A ) numbering schemes.
  • FIG. 8B shows protein sequence alignments of the heavy chain variable domain sequences of the VRC01 (SEQ ID NO: 5), VRC02 (SEQ ID NO: 197), VRC07 (SEQ ID NO: 2), VRC07b (SEQ ID NO: 3), VRC07c (SEQ ID NO: 4) and NI
  • FIGS. 8C-8C shows the protein sequence of the VRC01 light chain (SEQ ID NO: 9), with the Kabat and IMGT CDRs indicated.
  • FIGS. 8D-8F show a table indicating the linear and Kabat positioning of the amino acids of the VRC07 heavy chain variable domain and the VRC01 light chain variable domain.
  • FIG. 9 illustrates one strategy used to optimize the VRC07 monoclonal antibody.
  • FIG. 10 is a series of digital images illustrating the protein structure of VRC07 (with the indicated amino acid substitutions) binding to gp120, and also a series of graphs showing results of surface plasma resonance experiments concerning the binding of the VRC07 (with the indicated amino acid substitutions) to gp120.
  • FIG. 11 shows the protein sequence alignment of the heavy chain variable domains of the VRC01 (SEQ ID NO: 5), VRC07 (SEQ ID NO: 2), VRC07 G54W, I30Q (SEQ ID NO: 24), VRC07 G54W, I30R (SEQ ID NO: 25), VRC07 G54W, S58N (SEQ ID NO: 26) monoclonal antibodies.
  • the FR and CDR positions as determined using the IMGT and Kabat numbering schemes are shown.
  • FIGS. 12A-12B are a series of graphs illustrating the results of ELISA measurements of binding of the indicated monoclonal antibodies to the indicated gp120 proteins.
  • Tested monoclonal antibodies include antibodies with VRC07, VRC07(G54W), VRC07(G54W, I30Q), VRC07(G54W, I30R) and VRC07(G54W, S58N) heavy chains, each complemented with the VRC01 light chain.
  • FIGS. 13A-13D are a series of graphs illustrating the results of ELISA measurements of binding of the indicated monoclonal antibodies to the indicated gp120 proteins.
  • FIG. 14 is a set of tables showing the results of HIV-1 neutralization assays performed using monoclonal antibodies including the VRC07, v1_v7h3_m03_G54W, v1_v7h3_m02_G54W, VRC07(G54W), VRC07(G54W, I30Q), VRC07(G54W, I30R) or VRC07(G54W, S58N) heavy chains, each complemented with the VRC01 light chain. Neutralization was measured using the methods described Example 2.
  • FIGS. 15A-15LL are a series of graphs illustrating the results of ELISA measurements of binding of the indicated monoclonal antibodies to the indicated gp120 proteins (“con” stands for consensus sequence).
  • the heavy and light chains for each antibody are listed on top of each graph.
  • the y-axis is OD at 450 nm and the x-axis is antibody concentration in ⁇ g/ml.
  • the assay was performed in duplicate and values shown are an average.
  • Antibody heavy and light chain pairings chosen for further neutralization studies are underlined.
  • FIGS. 15V-15W “07” is an abbreviation for “VRC07” and all heavy chains were paired with VRC01 light chain).
  • FIGS. 15X-15EE “07” is an abbreviation for “VRC07ghv,” “01L” is an abbreviation for VRC01 light chain, and if no light chain is listed, VRC01 light chain was the light chain used.
  • FIGS. 16A-16B are a set of tables showing the results of HIV-1 neutralization assays performed using monoclonal antibodies formed from the indicated heavy and light chains.
  • FIG. 17 shows a sequence alignment illustrating the partial germline reversion and mutants of heavy chains variable domains.
  • the sequence of the following heavy chain variable domains is shown: VRC01gVH (SEQ ID NO: 198), VRC01ghvH03 (SEQ ID NO: 199), VRC01sVH (SEQ ID NO: 5), NIH4546ghvH01 (SEQ ID NO: 200), NIH4546ghvH02 (SEQ ID NO: 201) NIH4546sVH (SEQ ID NO: 196), VRC07gVH (SEQ ID NO: 202), VRC07ghvH01 (SEQ ID NO: 203), VRC07ghvH02 (SEQ ID NO: 204), VRC07ghvH04.1 (SEQ ID NO: 205), VRC07ghvH04.2 (SEQ ID NO: 206), VRC0ghvH05 (SEQ ID NO: 207), and VRC07sVH (VRC07
  • VRC01gVL (SEQ ID NO: 208), VRC01ghvL01 (SEQ ID NO: 209), VRC01ghvL02 (SEQ ID NO: 210), VRC01ghvL04 (SEQ ID NO: 211), VRC01N72T (SEQ ID NO: 212), VRC01ghvL05 (SEQ ID NO: 213), VRC01sVL (VRC01; SEQ ID NO: 9), NIH4546glvL01 (SEQ ID NO: 214), and NIH4546sVL (NIH4546; SEQ ID NO: 215).
  • FIG. 18 shows a sequence and a three dimensional structure illustrating the gp120 binding surface of the VRC01 monoclonal antibody and the residues of the VRC01 heavy and light chains that were selected for alanine scanning mutagenesis.
  • VRC01 binding energy hot spots (A) Amino acid sequence of VRC01 heavy chain variable domain (SEQ ID NO: 5). Bold letters indicate VRC01 residues contacting gp120. Single dot, double dot and triple dot below the amino acid sequence indicates positions that when mutated to alanine resulted in a significant decrease in affinity for gp120. Reduction in binding K D —single dot>double dot>triple dot.
  • FIGS. 19A-19C are a series of tables presenting affinity measurements for VRC01 monoclonal antibody (containing the indicated alanine substitution) binding to gp120 analyte RSC3 ( FIG. 19A ), gp120 from HIV-1 strain YU2 ( FIG. 19B ), and gp120 from HIV-1 strain ZM109 ( FIG. 19C ).
  • the calculated K D is indicated.
  • FIG. 20 is a set of bar graphs of an ELISA for VRC07 G54 heavy chain variants (the VRC07 G54 variant was complemented with VRC01 light chain).
  • the VRC07 G54 variant was complemented with VRC01 light chain.
  • G54F, G54R, G54W, and G54Y which showed improved binding to Glade A gp120s
  • G54A, G54H, G54K, G54M, and G54Q showed enhanced binding to two Glade A viruses tested; among them, G54H showed most improved biding to the gp120s.
  • FIG. 21 is a set of bar graphs of an ELISA for VRC07 G54 heavy chain variants (the VRC07 G54 variant was complemented with VRC01 light chain).
  • the VRC07 G54 variant was complemented with VRC01 light chain.
  • G54F, G54R, G54W, and G54Y which showed improved binding to Glade B gp120s, G54A, G54H, G54K, G54M, G54Q, and G54V showed enhanced binding to a Glade B or a Glade C virus.
  • FIG. 22 is a bar graph of an ELISA for VRC07 G54 heavy chain variants (the VRC07 G54 variant was complemented with VRC01 light chain).
  • the VRC07 G54 variant was complemented with VRC01 light chain.
  • G54F, G54R, G54W, and G54Y which showed improved binding to Du172 gp120s
  • G54A, G54H, G54K, G54M, and G54Q showed enhanced binding to the virus.
  • G54H showed most improved biding to the gp120 that is resistant to VRC01.
  • FIG. 23 is a table showing results from anti-cardiolipin assays of the indicated monoclonal antibodies. Anti-cardiolipin assays are used to indicate if an antibody is self-reactive. VRC07 heavy chain and the indicated variant VRC07 heavy chains were complemented with VRC01 light chain to form functional antibodies. The results indicate that a monoclonal antibody including the VRC07 G54H heavy chain variable domain and the VRC01 light chain variable domain is not autoreactive.
  • FIG. 24 is a set of tables showing results of neutralization experiments using antibodies including the indicated heavy and light chain variable domains.
  • the results indicate that an antibody including the VRC07 G54H variant heavy chain complemented with VRC01 light chain increased neutralization potency >2 fold compared to VRC07 heavy chain complemented with VRC01 light chain.
  • VRC07 G54H neutralizes the selected viruses more potently than VRC07.
  • the estimated fold improvement over VRC07 is about 2.3 and 2.5 fold when their geometric means of IC50 and IC80, respectively, are compared.
  • FIG. 25 shows a nucleic acid sequence encoding the VRC07 G54H heavy chain variable domain (SEQ ID NO: 37) and the amino acid sequence of the VRC07 G54H heavy chain variable domain (SEQ ID NO: 32).
  • FIG. 26 is a schematic diagram showing design of partially-reverted antibody variants.
  • FIG. 27 is a schematic diagram showing the design of partially-reverted antibody variants by CDR grafting.
  • FIG. 28 shows the sequences of partial revertants of VRC07 heavy chain and VRC01 light chain.
  • the sequence of the following heavy chain variable domains is shown: VRC01gVH (SEQ ID NO: 198), VRC07gVH (SEQ ID NO: 202), VRC07ghvH01 (SEQ ID NO: 203), VRC07ghvH02 (SEQ ID NO: 204), VRC07ghvH04.1 (SEQ ID NO: 205), VRC07ghvH04.2 (SEQ ID NO: 206), VRC07ghvH05 (SEQ ID NO: 207), VRC07ghvH05.1 (SEQ ID NO: 216), VRC07ghvH05.2 (SEQ ID NO: 217), VRC07ghvH05.3 (SEQ ID NO: 218), and VRC07sVH (SEQ ID NO: 2).
  • VRC01gVL (SEQ ID NO: 208), VRC01ghvL01 (SEQ ID NO: 209), VRC01ghvL02 (SEQ ID NO: 210), VRC01ghvL04 (SEQ ID NO: 211), VRC01_N72T (SEQ ID NO: 212), VRC01ghvL05 (SEQ ID NO: 213), and VRC01sVL (VRC01; SEQ ID NO: 9).
  • FIG. 29 is a table showing results of neutralization experiments using antibodies including the indicated heavy and light chains.
  • VRC07ghvH05.3 refers to VRC07 heavy chain with R3Q, I37V, and T93A amino acid substitutions.
  • VRC07ghvH05.3.1 refers to VRC07 heavy chain with I37C and T93A amino acid substitutions.
  • VRC01-EI-del refers to VRC01 light chain with the first two amino acids (E1 and I2) deleted.
  • FIG. 30 is a ribbon diagram of VRC07ghvH05.3 showing the R3Q, I37V, and T93A amino acid substitutions
  • FIG. 31 is a schematic diagram illustrating the deletion of the first two amino acids from the VRC01 light chain.
  • FIG. 32 is a table listing the VRC01/07 light chain variants.
  • FIG. 33 is a table showing results of neutralization experiments using antibodies including the indicated heavy and light chains. The results indicate the increased potency achieved with deletion of the first two amino acids of the light chain variable domain.
  • FIG. 34 is a table showing results of neutralization experiments using antibodies including the indicated heavy and light chains. The results indicate the increased potency achieved with deletion of the first two amino acids of the light chain variable domain.
  • nucleic and amino acid sequences listed in the accompanying sequence listing are shown using standard letter abbreviations for nucleotide bases, and three letter code for amino acids, as defined in 37 C.F.R. 1.822. Only one strand of each nucleic acid sequence is shown, but the complementary strand is understood as included by any reference to the displayed strand.
  • sequence.txt ⁇ 750 kb
  • SEQ ID NO: 1 is the amino acid sequence of the consensus heavy chain variable domain of the VRC07, VRC07b and VRC07c gp120 specific monoclonal antibodies with and without certain amino acid substitutions at positions I30, G54 and S58 (Kabat numbering).
  • SEQ ID NO: 2 is the amino acid sequence of the heavy chain variable domain of gp120-specific antibody VRC07.
  • SEQ ID NO: 3 is the amino acid sequence of the heavy chain variable domain of gp120-specific antibody VRC07b.
  • SEQ ID NO: 4 is the amino acid sequence of the heavy chain variable domain of gp120-specific antibody VRC07c.
  • SEQ ID NO: 5 is the amino acid sequence of the heavy chain variable domain of gp-120 specific antibody VRC01.
  • SEQ ID NO: 6 is the amino acid sequence of the consensus light chain variable domain of the VRC01, VRC07b and VRC07c gp120-specific antibodies.
  • SEQ ID NO: 7 is the amino acid sequence of the light chain variable domain of gp120-specific antibody VRC07b.
  • SEQ ID NO: 8 is the amino acid sequence of the light chain variable domain of gp120-specific antibody VRC07c.
  • SEQ ID NO: 9 is the amino acid sequence of the light chain variable domain of gp120-specific antibody VRC01.
  • SEQ ID NO: 10 is an exemplary nucleic acid sequence encoding the heavy chain variable domain of gp120-specific antibody VRC07.
  • SEQ ID NO: 11 is an exemplary nucleic acid sequence encoding the heavy chain variable domain of gp120-specific antibody VRC07b.
  • SEQ ID NO: 12 is an exemplary nucleic acid sequence encoding the heavy chain variable domain of gp120-specific antibody VRC07c.
  • SEQ ID NO: 13 an exemplary nucleic acid sequence encoding the heavy chain variable domain of gp-120 specific antibody VRC01.
  • SEQ ID NO: 14 is an exemplary nucleic acid sequence encoding the light chain variable domain of gp120-specific antibody VRC07b.
  • SEQ ID NO: 15 is an exemplary nucleic acid sequence encoding the light chain variable domain of gp120-specific antibody VRC07c.
  • SEQ ID NO: 16 is an exemplary nucleic acid sequence encoding the light chain variable domain of gp120-specific antibody VRC01.
  • SEQ ID NO: 17 is the nucleic acid sequence of a nucleic acid primer.
  • SEQ ID NO: 18 is the nucleic acid sequence of a nucleic acid primer.
  • SEQ ID NO: 19 is the nucleic acid sequence of a nucleic acid primer.
  • SEQ ID NO: 20 is the nucleic acid sequence of a nucleic acid primer.
  • SEQ ID NO: 21 is the nucleic acid sequence of a nucleic acid primer.
  • SEQ ID NO: 22 is the nucleic acid sequence of a nucleic acid primer.
  • SEQ ID NO: 23 is the amino acid sequence of the consensus heavy chain variable domain for VRC07 gp120 specific monoclonal antibodies with certain amino acid substitutions at positions I30, G54 and S58 (Kabat numbering).
  • SEQ ID NO: 24 is the amino acid sequence of the heavy chain variable domain of gp120-specific antibody VRC07 G54W, I30Q.
  • SEQ ID NO: 25 is the amino acid sequence of the heavy chain variable domain of gp120-specific antibody VRC07 G54W, I30R.
  • SEQ ID NO: 26 is the amino acid sequence of the heavy chain variable domain of gp120-specific antibody VRC07 G54W, S58N.
  • SEQ ID NO: 27 is the amino acid sequence of the light chain variable domain of the gp120-specific antibody VRC01 N72A.
  • SEQ ID NO: 28 is the amino acid sequence of the heavy chain variable domain of gp120-specific antibody VRC07 G54W.
  • SEQ ID NO: 29 is the amino acid sequence of the consensus heavy chain of the VRC07, VRC07b and VRC07c gp120 specific antibodies.
  • SEQ ID NO: 30 is the amino acid sequence of the heavy chain variable domain of the gp120 specific antibody VRC07 with a A, F, H, K, M, Q, R, V, W, or Y amino acid substitution at Kabat position G54.
  • SEQ ID NO: 31 is the amino acid sequence of the heavy chain variable domain of the gp120 specific antibody VRC07 G54A.
  • SEQ ID NO: 32 is the amino acid sequence of the heavy chain variable domain of the gp120 specific antibody VRC07 G54H.
  • SEQ ID NO: 33 is the amino acid sequence of the heavy chain variable domain of the gp120 specific antibody VRC07 G54K.
  • SEQ ID NO: 34 is the amino acid sequence of the heavy chain variable domain of the gp120 specific antibody VRC07 G54M.
  • SEQ ID NO: 35 is the amino acid sequence of the heavy chain variable domain of the gp120 specific antibody VRC07 G54Q.
  • SEQ ID NO: 36 is the amino acid sequence of the heavy chain variable domain of the gp120 specific antibody VRC07 G54V.
  • SEQ ID NO: 37 is a nucleic acid sequence encoding VRC07 G54H (see FIG. 25 ).
  • SEQ ID NO: 38 is the amino acid sequence of a consensus VRC07 heavy chain with partial germline reversions.
  • SEQ ID NO: 39 is the amino acid sequence of VRC07 heavy chain with three amino acids reverted to the germline.
  • SEQ ID NO: 40 is the consensus amino acid sequence of a heavy chain of VRC07 with amino acid substitutions at one or more of positions I37, G54, S58, and T93 (Kabat numbering).
  • SEQ ID NO: 41 is the amino acid sequence of a consensus VRC07 light chain.
  • X 1 is E or no amino acid
  • X 2 is I or no amino acid
  • X 3 is T or I
  • X 4 is W or S
  • X 5 is N or T
  • X 6 is V or Q
  • X 7 is I or N.
  • SEQ ID NO: 42 is the amino acid sequence of a consensus VRC07 light chain.
  • X 1 is E, G, A or no amino acid
  • X 2 is I, G, A, or no amino acid
  • X 3 is V, G, A or no amino acid
  • X 4 is L, G, A or no amino acid
  • X 5 is N, F or T.
  • SEQ ID NO: 43 is the consensus amino acid sequence of a light chain variable domain.
  • SEQ ID NO: 44 is the consensus amino acid sequence of a light chain variable domain.
  • SEQ ID NO: 45 is the amino acid sequence of a peptide.
  • SEQ ID NO: 46 is the amino acid sequence of a peptide.
  • SEQ ID NO: 47 is the amino acid sequence of a peptide.
  • SEQ ID NO: 48 is the amino acid sequence of a peptide linker
  • SEQ ID NO: 49 is the nucleotide sequence of an oligonucleotide.
  • SEQ ID NO: 50 is the amino acid sequence of the VRC01hpL02 light chain variable domain.
  • SEQ ID NO: 51 is the amino acid sequence of the VRC01ghvL05 light chain variable domain.
  • SEQ ID NO: 53 is the amino acid sequence of the VRC01 light chain variable domain with deletion of the E1 and I2 amino acids.
  • SEQ ID NO: 54 is the amino acid sequence of the VRC01 light chain variable domain with deletion of the E1 and I2 amino acids, and a N72T amino acid substitution.
  • SEQ ID NO: 55 is the amino acid sequence of the VRC01hpL02 light chain variable domain.
  • SEQ ID NO: 56 is the amino acid sequence of the VRC01hpL02 light chain variable domain with deletion of the E1 and I2 amino acids.
  • SEQ ID NOs: 57-100 are the nucleotide sequences of plasmids and plasmid inserts encoding VRC07 heavy chain variants, as indicated in Table 2.
  • SEQ ID Nos: 101-108 are the nucleotide and protein sequences of VRC07 heavy chain variants, as indicated in Table 3.
  • SEQ ID NOs: 109-194 are the nucleotide sequences of plasmids and plasmid inserts encoding VRC07 heavy chain and VRC01 light chain variants, as indicated in Table 2.
  • SEQ ID NO: 195 is the amino acid sequence of IGHV1-2*02 germline.
  • SEQ ID NO: 196 is the amino acid sequence of the heavy chain variable domain of VRC4546.
  • SEQ ID NO: 197 is the amino acid sequence of the heavy chain variable domain of VRC02.
  • SEQ ID NO: 198 is the amino acid sequence of VRC01 heavy chain germline sequence (VRC01_gVH).
  • SEQ ID NO: 199 is the amino acid sequence of the VRC01_ghvH03 heavy chain variable domain.
  • SEQ ID NO: 200 is the amino acid sequence of the VRC4546ghvH01 heavy chain variable domain.
  • SEQ ID NO: 201 is the amino acid sequence of the VRC4546ghvH02 heavy chain variable domain.
  • SEQ ID NO: 202 is the amino acid sequence of the VRC07_gVH germline sequence.
  • SEQ ID NO: 203 is the amino acid sequence of the VRC07ghvH01 heavy chain variable domain.
  • SEQ ID NO: 204 is the amino acid sequence of the VRC07ghvH02 heavy chain variable domain.
  • SEQ ID NO: 205 is the amino acid sequence of the VRC07ghvH04.1 heavy chain variable domain.
  • SEQ ID NO: 206 is the amino acid sequence of the VRC07ghvH04.2 heavy chain variable domain.
  • SEQ ID NO: 207 is the amino acid sequence of the VRC07ghvH05 heavy chain variable domain.
  • SEQ ID NO: 208 is the amino acid sequence of the VRC01gVL germline.
  • SEQ ID NO: 209 is the amino acid sequence of the VRC01ghvL01 light chain variable domain.
  • SEQ ID NO: 210 is the amino acid sequence of the VRC01ghvL02 light chain variable domain.
  • SEQ ID NO: 211 is the amino acid sequence of the VRC01ghvL04 light chain variable domain.
  • SEQ ID NO: 212 is the amino acid sequence of the VRC01N72T light chain variable domain.
  • SEQ ID NO: 213 is the amino acid sequence of the VRC01ghvL05 light chain variable domain.
  • SEQ ID NO: 214 is the amino acid sequence of the VRC4546ghvL01 light chain variable domain.
  • SEQ ID NO: 215 is the amino acid sequence of the VRC4546L light chain variable domain.
  • SEQ ID NO: 216 is the amino acid sequence of the VRC07ghvH05.1 heavy chain variable domain.
  • SEQ ID NO: 217 is the amino acid sequence of the VRC07ghvH05.2 heavy chain variable domain.
  • SEQ ID NO: 218 is the amino acid sequence of the VRC07ghvH05.3 heavy chain variable domain.
  • SEQ ID NO: 219 is the amino acid sequence of the VRC01 E1/I2del V3E light chain variable domain.
  • SEQ ID NO: 220 is the amino acid sequence of the VRC01 E1/I2del V3K light chain variable domain.
  • SEQ ID NO: 221 is the amino acid sequence of the VRC01 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 222 is the amino acid sequence of the VRC01 E1/I2del F97D light chain variable domain.
  • SEQ ID NO: 223 is the amino acid sequence of the VRC01 E1/I2del F97K light chain variable domain.
  • SEQ ID NO: 224 is the amino acid sequence of the VRC01 E1/I2del F97S light chain variable domain.
  • SEQ ID NO: 225 is the amino acid sequence of the VRC01 E1/I2del F97H light chain variable domain.
  • SEQ ID NO: 226 is the amino acid sequence of the VRC01 E1/I2del V3E/F97S light chain variable domain.
  • SEQ ID NO: 227 is the amino acid sequence of the VRC01 E1/I2del V3E/F97H light chain variable domain.
  • SEQ ID NO: 228 is the amino acid sequence of the VRC01hpL03 light chain variable domain.
  • SEQ ID NO: 229 is the amino acid sequence of the VRC01hpL04 light chain variable domain.
  • SEQ ID NO: 230 is the amino acid sequence of the VRC01hpL05 light chain variable domain.
  • SEQ ID NO: 231 is the amino acid sequence of the VRC01hpL06 light chain variable domain.
  • SEQ ID NO: 232 is the amino acid sequence of the VRC01hpL02 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 233 is the amino acid sequence of the VRC01 hpL03 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 234 is the amino acid sequence of the VRC01 hpL04 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 235 is the amino acid sequence of the VRC01hpL05 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 236 is the amino acid sequence of the VRC01hpL06 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 237 is the amino acid sequence of the VRC01hpL04 E1/I2del V3E light chain variable domain.
  • SEQ ID NO: 238 is a consensus amino acid sequence of the VRC01 light chain variable domain with one or more amino acid substitutions or deletions.
  • SEQ ID NO: 239 is the amino acid sequence of an antibody light chain including the VRC01 E1/I2del V3E light chain variable domain.
  • SEQ ID NO: 240 is the amino acid sequence of an antibody light chain including the VRC01 E1/I2del V3K light chain variable domain.
  • SEQ ID NO: 241 is the amino acid sequence of an antibody light chain including the VRC01 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 242 is the amino acid sequence of an antibody light chain including the VRC01 E1/I2del F97D light chain variable domain.
  • SEQ ID NO: 243 is the amino acid sequence of an antibody light chain including the VRC01 E1/I2del F97K light chain variable domain.
  • SEQ ID NO: 244 is the amino acid sequence of an antibody light chain including the VRC01 E1/I2del F97S light chain variable domain.
  • SEQ ID NO: 245 is the amino acid sequence of an antibody light chain including the VRC01 E1/I2del F97H light chain variable domain.
  • SEQ ID NO: 246 is the amino acid sequence of an antibody light chain including the VRC01 E1/I2del V3E/F97S light chain variable domain.
  • SEQ ID NO: 247 is the amino acid sequence of an antibody light chain including the VRC01 E1/I2del V3E/F97H light chain variable domain.
  • SEQ ID NO: 248 is the amino acid sequence of an antibody light chain including the VRC01hpL03 light chain variable domain.
  • SEQ ID NO: 249 is the amino acid sequence of an antibody light chain including the VRC01hpL04 light chain variable domain.
  • SEQ ID NO: 250 is the amino acid sequence of an antibody light chain including the VRC01hpL05 light chain variable domain.
  • SEQ ID NO: 251 is the amino acid sequence of an antibody light chain including the VRC01hpL06 light chain variable domain.
  • SEQ ID NO: 252 is the amino acid sequence of an antibody light chain including the VRC01hpL02 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 253 is the amino acid sequence of an antibody light chain including the VRC01hpL03 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 254 is the amino acid sequence of an antibody light chain including the VRC01hpL04 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 255 is the amino acid sequence of an antibody light chain including the VRC01hpL05 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 256 is the amino acid sequence of an antibody light chain including the VRC01hpL06 E1/I2del V3S light chain variable domain.
  • SEQ ID NO: 257 is the amino acid sequence of an antibody light chain including the VRC01hpL04 E1/I2del V3E light chain variable domain.
  • SEQ ID NO: 258 is the amino acid sequence of the VRC07 G54H S58N heavy chain variable domain.
  • SEQ ID NO: 259 is the amino acid sequence of the VRC07 I37V G54H T93A heavy chain variable domain.
  • SEQ ID NO: 260 is the amino acid sequence of the VRC07 I37V G54H S58N T93A heavy chain variable domain.
  • bNAbs Broadly neutralizing HIV-1 antibodies
  • bNAbs target conserved sites of vulnerability on the HIV-1 envelope (env) such as the CD4 binding site (CD4bs).
  • CD4bs CD4 binding site
  • the b12 monoclonal antibody was for many years considered the prototype and optimal CD4bs bNAb, although it was only able to neutralize ⁇ 40% of HIV-1 strains.
  • a new group of CD4bs antibodies named VRC01, VRC02, and VRC03 was disclosed. Of these, VRC01 was the most potent and broad.
  • VRC01 neutralized 91% of viruses with an IC 50 less than 50 ⁇ g/ml and 72% of viruses with an IC 50 less than 1 ⁇ g/ml (Wu et al., Science, 329(5993):856-861, 2010). Structural analyses have explained VRC01's high potency and breadth: VRC01 partially mimics the CD4 interaction with gp120. Specifically, the majority of the gp120 area targeted by VRC01 is the highly conserved site of initial CD4 attachment in the outer domain of gp120, which allows VRC01 to bypass conformational and glycan masking that impaired previously identified CD4bs bNAbs.
  • VRC01 Both the heavy and light chain of VRC01 contribute to the binding of gp120, with the CDRH2 providing the primary interaction, and CDRL1, CDRL3, CDRH1, and CDRH3 providing additional contact points. It has been shown that passive transfer of VRC01 protects against intrarectal or intravaginal simian-HIV (SHIV) challenge in non-human primates.
  • SHIV intravaginal simian-HIV
  • VRC01 Despite the success of VRC01, there is a need for additional broadly neutralizing antibodies that can inhibit HIV infection, particularly broadly neutralizing antibodies that have increased affinity for gp120, but not increase reactivity towards self antigens, compared to VRC01.
  • VRC07 monoclonal antibody which specifically binds to the CD4 binding site of the gp120 protein of HIV, and is neutralizing VRC07 is a VRC01-like monoclonal antibody, and includes a novel heavy chain (“VRC07 heavy chain”) cross complemented with the light chain of the VRC01 monoclonal antibody.
  • VRC07 has increased binding affinity for gp120, but does not have significantly increased self-reactivity, for example, compared to VRC01.
  • variants of the VRC07 heavy chain and the VRC01 light chain and cross-complemented monoclonal antibodies including such variants that have increased binding affinity for gp120, but are not self-reactive or have low self reactivity compared to a control.
  • the disclosed variants of the VRC07 heavy chain and the VRC01 light chain include framework region amino acid substitutions (compared to VRC07 heavy chain or VRC01 light chain), but only include up to two amino acid substitutions in the CDRs (compared to VRC07 heavy chain or VRC01 light chain).
  • the disclosed antibodies further are not immunogenic, or have low immunogenicity.
  • the term “comprises” means “includes.”
  • “comprising an antigen” means “including an antigen” without excluding other elements.
  • Administration The introduction of a composition into a subject by a chosen route. Administration can be local or systemic. For example, if the chosen route is intravenous, the composition is administered by introducing the composition into a vein of the subject. In some examples a disclosed antibody specific for an HIV protein or polypeptide, or a nucleic acid encoding the antibody, is administered to a subject.
  • Agent Any substance or any combination of substances that is useful for achieving an end or result; for example, a substance or combination of substances useful for inhibiting HIV infection in a subject.
  • Agents include proteins, nucleic acid molecules, compounds, small molecules, organic compounds, inorganic compounds, or other molecules of interest.
  • An agent can include a therapeutic agent (such as an anti-retroviral agent), a diagnostic agent or a pharmaceutical agent.
  • the agent is a polypeptide agent (such as a HIV-neutralizing antibody), or an anti-viral agent.
  • a polypeptide agent such as a HIV-neutralizing antibody
  • Amino acid substitution The replacement of one amino acid in a polypeptide with a different amino acid.
  • Amplification A technique that increases the number of copies of a nucleic acid molecule (such as an RNA or DNA).
  • An example of amplification is the polymerase chain reaction, in which a biological sample is contacted with a pair of oligonucleotide primers, under conditions that allow for the hybridization of the primers to a nucleic acid template in the sample.
  • the primers are extended under suitable conditions, dissociated from the template, and then re-annealed, extended, and dissociated to amplify the number of copies of the nucleic acid.
  • the product of amplification can be characterized by electrophoresis, restriction endonuclease cleavage patterns, oligonucleotide hybridization or ligation, and/or nucleic acid sequencing using standard techniques.
  • Other examples of amplification include strand displacement amplification, as disclosed in U.S. Pat. No. 5,744,311; transcription-free isothermal amplification, as disclosed in U.S. Pat. No. 6,033,881; repair chain reaction amplification, as disclosed in WO 90/01069; ligase chain reaction amplification, as disclosed in EP-A-320 308; gap filling ligase chain reaction amplification, as disclosed in U.S. Pat. No. 5,427,930; and NASBATM RNA transcription-free amplification, as disclosed in U.S. Pat. No. 6,025,134.
  • Animal Living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds.
  • mammal includes both human and non-human mammals.
  • subject includes both human and veterinary subjects.
  • Antibody A polypeptide substantially encoded by an immunoglobulin gene or immunoglobulin genes, or antigen binding fragments thereof, which specifically binds and recognizes an analyte (antigen) such as gp120 or an antigenic fragment of gp120.
  • Immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable domain genes.
  • Antibodies exist, for example as intact immunoglobulins and as antigen binding fragments produced by digestion with various peptidases. For instance, Fabs, Fvs, and single-chain Fvs (scFvs) that specifically bind to gp120 or fragments of gp120 (that include the epitope bound by the originating antibody) would be gp120-specific binding agents.
  • a scFv protein is a fusion protein in which a light chain variable domain of an immunoglobulin and a heavy chain variable domain of an immunoglobulin are bound by a linker, while in dsFvs, the chains have been mutated to introduce a disulfide bond to stabilize the association of the chains.
  • the term also includes genetically engineered forms such as chimeric antibodies (such as humanized murine antibodies), heteroconjugate antibodies such as bispecific antibodies). See also, Pierce Catalog and Handbook, 1994-1995 (Pierce Chemical Co., Rockford, Ill.); Kuby, J., Immunology, 3 rd Ed., W.H. Freeman & Co., New York, 1997.
  • antigen-binding antibody fragments include: (1) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molecule produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain; (2) Fab′, the fragment of an antibody molecule obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab′ fragments are obtained per antibody molecule; (3) (Fab′) 2 , the fragment of the antibody obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; (4) F(ab′) 2 , a dimer of two Fab′ fragments held together by two disulfide bonds; (5) Fv, a genetically engineered fragment containing the variable domain of the light chain and the variable domain of the heavy chain expressed as two chains; and (6) single chain antibody (“SCA”), a genetically engineered molecule containing the variable domain of the light chain, the variable domain of the heavy chain, linked by a suitable polypeptid
  • a naturally occurring immunoglobulin has heavy (H) chains and light (L) chains interconnected by disulfide bonds.
  • H heavy chain
  • L light chain
  • ⁇ lambda
  • ⁇ kappa
  • IgM immunoglobulin heavy chain classes
  • Each heavy and light chain contains a constant region and a variable region, (the regions are also known as “domains”).
  • the heavy and the light chain variable domains combine to specifically bind the antigen.
  • only the heavy chain variable domain is required.
  • naturally occurring camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain (see, e.g., Hamers-Casterman et al., Nature, 363:446-448, 1993; Sheriff et al., Nat. Struct. Biol., 3:733-736, 1996).
  • Light and heavy chain variable domains contain a “framework” region interrupted by three hypervariable regions, also called “complementarity-determining regions” or “CDRs” (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest , U.S. Department of Health and Human Services, 1991).
  • CDRs complementarity-determining regions
  • the sequences of the framework regions of different light or heavy chains are relatively conserved within a species.
  • the framework region of an antibody that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs in three-dimensional space.
  • the CDRs are primarily responsible for binding to an epitope of an antigen.
  • the amino acid sequence boundaries of a given CDR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (“Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991; “Kabat” numbering scheme), Al-Lazikani et al., (JMB 273,927-948, 1997; “Chothia” numbering scheme), and Lefranc et al. (“IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev. Comp. Immunol., 27:55-77, 2003; “IMGT” numbering scheme).
  • the CDRs of each chain are typically referred to as CDR1, CDR2, and CDR3 (from the N-terminus to C-terminus), and are also typically identified by the chain in which the particular CDR is located.
  • a V H CDR3 is the CDR3 from the variable domain of the heavy chain of the antibody in which it is found
  • a V L CDR1 is the CDR1 from the variable domain of the light chain of the antibody in which it is found.
  • Light chain CDRs are sometimes referred to as LCDR1, LCDR2, and LCDR3.
  • Heavy chain CDRs are sometimes referred to as LCDR1, LCDR2, and LCDR3.
  • V H refers to the variable domain of an immunoglobulin heavy chain, including that of an antibody fragment, such as Fv, scFv, dsFv or Fab.
  • V L refers to the variable domain of an immunoglobulin light chain, including that of an Fv, scFv, dsFv or Fab.
  • a “monoclonal antibody” is an antibody produced by a single clone of B-lymphocytes or by a cell into which the light and heavy chain genes of a single antibody have been transfected.
  • Monoclonal antibodies are produced by methods known to those of skill in the art, for instance by making hybrid antibody-forming cells from a fusion of myeloma cells with immune spleen cells. These fused cells and their progeny are termed “hybridomas.”
  • Monoclonal antibodies include humanized and fully human monoclonal antibodies. In some examples monoclonal antibodies are isolated from a subject. The amino acid sequences of such isolated monoclonal antibodies can be determined.
  • a “humanized” immunoglobulin is an immunoglobulin including a human framework region and one or more CDRs from a non-human (such as a mouse, rat, or synthetic) immunoglobulin.
  • the non-human immunoglobulin providing the CDRs is termed a “donor,” and the human immunoglobulin providing the framework is termed an “acceptor.”
  • all the CDRs are from the donor immunoglobulin in a humanized immunoglobulin.
  • Constant regions need not be present, but if they are, they must be substantially identical to human immunoglobulin constant regions, such as at least about 85-90%, such as about 95% or more identical.
  • a “humanized antibody” is an antibody including a humanized light chain and a humanized heavy chain immunoglobulin.
  • a humanized antibody binds to the same antigen as the donor antibody that provides the CDRs.
  • the acceptor framework of a humanized immunoglobulin or antibody may have a limited number of substitutions by amino acids taken from the donor framework.
  • Humanized or other monoclonal antibodies can have additional conservative amino acid substitutions, such as in the framework region, which have substantially no effect on antigen binding or other immunoglobulin functions.
  • Humanized immunoglobulins can be constructed by means of genetic engineering (for example, see U.S. Pat. No. 5,585,089).
  • Antibody Scaffold Refers to a heterologous protein that is engrafted with one or more CDRs from an antibody of interest on its surface. Transplantation of the CDRs can performed computationally in a manner that preserves its relevant structure and conformation. Mutations within the acceptor scaffold are made in order to accommodate the CDR graft.
  • Antibody Immunogenicity A property of an antibody, whereby the antibody generates an immune response when administered to a subject, such as a human subject.
  • a disclosed antibody is not immunogenic or has low immunogenicity, for example, a disclosed antibody is not significantly more immunogenic compared to a standard control, or a reference antibody.
  • Methods of determining the immunogenicity of an antibody are known to the person of ordinary skill in the art (see, e.g., Krieckaert et al., Current Opin Rheumatol., 24:306-311, 2012; Stas and Lasters, IDrugs, 12:169-173, 2009).
  • immunogenicity can be determined by assaying plasma or serum from a test subject using an ELISA against the antibody of interest.
  • Antibody self-reactivity or autoreactivity A property of an antibody, whereby the antibody reacts with self-epitopes, that is epitopes of proteins and/or lipids that are produced by the subject.
  • An antibody that does not have self-reactivity does not substantially bind to epitopes or lipids present on the membrane of a cell from a subject.
  • Methods of determining if an antibody reacts with self epitopes are known to the person of ordinary skill in the art and described herein (for example, in Examples 1 and 8).
  • antibody self reactivity is evaluated using an anti-cardiolipin assay or an anti-nuclear antigen (ANA) assay.
  • ANA anti-nuclear antigen
  • the anti-ANA assay can include an anti-ANA LUMINEX® assay or an ANA cell-staining assay, for example.
  • a disclosed antibody is not self-reactive (or autoreactive), or is minimally self-reactive.
  • a disclosed antibody is not significantly more self-reactive compared to the VRC01 antibody, for example as measured using an anti-ANA LUMINEX® assay or an ANA cell-staining assay.
  • a disclosed antibody noes not have self reactivity above background levels, for example, as measured using an anti-ANA LUMINEX® assay or an ANA cell-staining assay.
  • Antigen A polypeptide that can stimulate the production of antibodies or a T cell response in an animal, including polypeptides that are injected or absorbed into an animal.
  • An antigen reacts with the products of specific humoral or cellular immunity, including those induced by heterologous antigens, such as the disclosed antigens.
  • Epitope or “antigenic determinant” refers to the region of an antigen to which B and/or T cells respond.
  • T cells respond to the epitope, when the epitope is presented in conjunction with an MHC molecule.
  • Epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein.
  • Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents.
  • An epitope typically includes at least 3, and more usually, at least 5, about 9, or about 8-10 amino acids in a unique spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and nuclear magnetic resonance.
  • Immunogenic polypeptides and immunogenic peptides are non-limiting examples of antigens.
  • antigens include polypeptides derived from a pathogen of interest, such as a virus.
  • An antigen that can stimulate the production of antibodies or a T cell response in a subject to a polypeptide expressed by a virus is a viral antigen.
  • An “HIV antigen” can stimulate the production of antibodies or a T cell response in a subject to a polypeptide expressed by HIV.
  • an HIV antigen is a polypeptide expressed by HIV, such as HIV ENV, or a fragment thereof, such as gp120.
  • a “target epitope” is a specific epitope on an antigen that specifically binds an antibody of interest, such as a monoclonal antibody.
  • a target epitope includes the amino acid residues that contact the antibody of interest, such that the target epitope can be selected by the amino acid residues determined to be in contact with the antibody of interest.
  • Antigenic surface A surface of a molecule, for example a protein such as a gp120 protein or polypeptide, capable of eliciting an immune response.
  • An antigenic surface includes the defining features of that surface, for example the three-dimensional shape and the surface charge.
  • An antigenic surface includes both surfaces that occur on gp120 polypeptides as well as surfaces of compounds that mimic the surface of a gp120 polypeptide (mimetics).
  • an antigenic surface includes all or part of the surface of gp120 that binds to the CD4 receptor.
  • Anti-retroviral agent An agent that specifically inhibits a retrovirus from replicating or infecting cells.
  • antiretroviral drugs include entry inhibitors (e.g., enfuvirtide), CCR5 receptor antagonists (e.g., aplaviroc, vicriviroc, maraviroc), reverse transcriptase inhibitors (e.g., lamivudine, zidovudine, abacavir, tenofovir, emtricitabine, efavirenz), protease inhibitors (e.g., lopivar, ritonavir, raltegravir, darunavir, atazanavir), maturation inhibitors (e.g., alpha interferon, bevirimat and makecon).
  • entry inhibitors e.g., enfuvirtide
  • CCR5 receptor antagonists e.g., aplaviroc, vicriviroc, maraviroc
  • Anti-retroviral therapy A therapeutic treatment for HIV infection involving administration of at least one anti-retroviral agents (e.g., one, two, three or four anti-retroviral agents) to an HIV infected individual during a course of treatment.
  • at least one anti-retroviral agents e.g., one, two, three or four anti-retroviral agents
  • Non-limiting examples of antiretroviral agents include entry inhibitors (e.g., enfuvirtide), CCR5 receptor antagonists (e.g., aplaviroc, vicriviroc, maraviroc), reverse transcriptase inhibitors (e.g., lamivudine, zidovudine, abacavir, tenofovir, emtricitabine, efavirenz), protease inhibitors (e.g., lopivar, ritonavir, raltegravir, darunavir, atazanavir), maturation inhibitors (e.g., alpha interferon, bevirimat and makecon).
  • entry inhibitors e.g., enfuvirtide
  • CCR5 receptor antagonists e.g., aplaviroc, vicriviroc, maraviroc
  • reverse transcriptase inhibitors e.g., lamivudine, zidovudine, a
  • Atomic Coordinates or Structure coordinates Mathematical coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays by the atoms (scattering centers) such as an antigen, or an antigen in complex with an antibody.
  • antigen can be gp120, a gp120:antibody complex, or combinations thereof in a crystal.
  • the diffraction data are used to calculate an electron density map of the repeating unit of the crystal.
  • the electron density maps are used to establish the positions of the individual atoms within the unit cell of the crystal.
  • structure coordinates refers to Cartesian coordinates derived from mathematical equations related to the patterns obtained on diffraction of a monochromatic beam of X-rays, such as by the atoms of a gp120 in crystal form.
  • any set of structure coordinates determined by X-ray crystallography is not without standard error.
  • Binding affinity Affinity of an antibody or antigen binding fragment thereof for an antigen.
  • affinity is calculated by a modification of the Scatchard method described by Frankel et al., Mol. Immunol., 16:101-106, 1979.
  • binding affinity is measured by an antigen/antibody dissociation rate.
  • a high binding affinity is measured by a competition radioimmunoassay.
  • a high binding affinity is at least about 1 ⁇ 10 ⁇ 8 M.
  • a high binding affinity is at least about 1.0 ⁇ 10 ⁇ 8 , at least about 5.0 ⁇ 10 ⁇ 8 , at least about 1.0 ⁇ 10 ⁇ 9 , at least about 1.5 ⁇ 10 ⁇ 9 , at least about 2.0 ⁇ 10 ⁇ 9 , at least about 2.5 ⁇ 10 ⁇ 9 , or at least about 3.0 ⁇ 10 ⁇ 9 .
  • Bispecific antibody A recombinant molecule composed of two different antigen binding domains that consequently bind to two different antigenic epitopes.
  • Bispecific antibodies include chemically or genetically linked molecules of two antigen-binding domains.
  • the antigen binding domains can be linked using a linker.
  • the antigen binding domains can be monoclonal antibodies, antigen-binding fragments (e.g., Fab, scFv), eAds, bispecific single chain antibodies or combinations thereof.
  • a bispecific antibody can include one or more constant domains, but does not necessarily include a constant domain.
  • bispecific antibody is a bispecific single chain antibody including a scFv that specifically binds to gp120 joined (via a peptide linker) to a scFv that specifically binds to an antigen other than gp120.
  • a bispecific antibody including a Fab that specifically binds to gp120 joined to a scFv that specifically binds to an antigen other than gp120.
  • CD4 Cluster of differentiation factor 4 polypeptide; a T-cell surface protein that mediates interaction with the MHC class II molecule. CD4 also serves as the primary receptor site for HIV on T-cells during HIV infection. CD4 is known to bind to gp120 from HIV. The known sequence of the CD4 precursor has a hydrophobic signal peptide, an extracellular region of approximately 370 amino acids, a highly hydrophobic stretch with significant identity to the membrane-spanning domain of the class II MHC beta chain, and a highly charged intracellular sequence of 40 resides (Maddon, Cell 42:93, 1985).
  • CD4 includes polypeptide molecules that are derived from CD4 include fragments of CD4, generated either by chemical (for example enzymatic) digestion or genetic engineering means. Such a fragment may be one or more entire CD4 protein domains.
  • the extracellular domain of CD4 consists of four contiguous immunoglobulin-like regions (D1, D2, D3, and D4, see Sakihama et al., Proc. Natl. Acad. Sci. 92:6444, 1995; U.S. Pat. No. 6,117,655), and amino acids 1 to 183 have been shown to be involved in gp120 binding.
  • a binding molecule or binding domain derived from CD4 would include a sufficient portion of the CD4 protein to mediate specific and functional interaction between the binding fragment and a native or viral binding site of CD4.
  • One such binding fragment includes both the D1 and D2 extracellular domains of CD4 (D1D2 is also a fragment of soluble CD4 or sCD4 which is comprised of D1 D2 D3 and D4), although smaller fragments may also provide specific and functional CD4-like binding.
  • the gp120-binding site has been mapped to D1 of CD4.
  • CD4 polypeptides also include “CD4-derived molecules” which encompasses analogs (non-protein organic molecules), derivatives (chemically functionalized protein molecules obtained starting with the disclosed protein sequences) or mimetics (three-dimensionally similar chemicals) of the native CD4 structure, as well as proteins sequence variants or genetic alleles that maintain the ability to functionally bind to a target molecule.
  • CD4-derived molecules encompasses analogs (non-protein organic molecules), derivatives (chemically functionalized protein molecules obtained starting with the disclosed protein sequences) or mimetics (three-dimensionally similar chemicals) of the native CD4 structure, as well as proteins sequence variants or genetic alleles that maintain the ability to functionally bind to a target molecule.
  • CD4 binding site (CD4BS) antibodies Antibodies that bind to or substantially overlap the CD4 binding surface of a gp120 polypeptide. The antibodies interfere with or prevent CD4 from binding to a gp120 polypeptide.
  • Chimeric antibody An antibody which includes sequences derived from two different antibodies, such as from different species.
  • a chimeric antibody includes one or more CDRs and/or framework regions from one human antibody and CDRs and/or framework regions from another human antibody.
  • Clonal variant Any sequence, which differs by one or more nucleotides or amino acids, in presence of V region with identical mutations compared to the germline, identical VDJ or VJ gene usage, and identical D and J length.
  • the “germline” sequence is intended to be the sequence coding for the antibody/immunoglobulin (or of any fragment thereof) deprived of mutations, for example somatic mutations.
  • the percentage of homology represents an indication of the mutational events which any type of heavy chain portion undergoes after contact with an antigen.
  • Conjugate A complex of two molecules linked together, for example, linked together by a covalent bond.
  • an antibody is linked to an effector molecule; for example, an antibody that specifically binds to gp120 covalently linked to an effector molecule or to a toxin.
  • the linkage can be by chemical or recombinant means.
  • the linkage is chemical, wherein a reaction between the antibody moiety and the effector molecule has produced a covalent bond formed between the two molecules to form one molecule.
  • a peptide linker short peptide sequence
  • conjugates can be prepared from two molecules with separate functionalities, such as an antibody and an effector molecule, they are also sometimes referred to as “chimeric molecules.”
  • an antibody linked to an effector molecule is further joined to a lipid or other molecule to a protein or peptide to increase its half-life in the body.
  • Placement in direct physical association includes both in solid and liquid form, which can take place either in vivo or in vitro.
  • Contacting includes contact between one molecule and another molecule, for example the amino acid on the surface of one polypeptide, such as an antigen, that contacts another polypeptide, such as an antibody.
  • Contacting can also include contacting a cell for example by placing an antibody in direct physical association with a cell.
  • Control A reference standard.
  • the control is a negative control, such as sample obtained from a healthy patient not infected with HIV.
  • the control is a positive control, such as a tissue sample obtained from a patient diagnosed with HIV infection.
  • the control is a historical control or standard reference value or range of values (such as a previously tested control sample, such as a group of HIV patients with known prognosis or outcome, or group of samples that represent baseline or normal values).
  • a difference between a test sample and a control can be an increase or conversely a decrease.
  • the difference can be a qualitative difference or a quantitative difference, for example a statistically significant difference.
  • a difference is an increase or decrease, relative to a control, of at least about 5%, such as at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, or at least about 500%.
  • Cross complementation Formation of an antibody including a heavy and light chain variable domains using a heavy chain variable domain of an antibody that specifically binds an epitope of an antigen of interest from first antibody and a light chain variable domain of an antibody that specifically binds the same epitope from a second antibody, wherein the antibody that is formed from the heavy chain variable domain and the light chain variable domain retains its ability to bind the epitope and wherein the first and the second antibodies are different antibodies.
  • the light chain variable domains and the heavy chain variable domains that form an antibody are from different sources, but the chimeric antibody that is formed still binds the epitope.
  • the antigen is gp120.
  • an antibody that specifically binds to gp120 includes a heavy chain cross-complemented with a light chain, wherein the heavy chain includes the heavy chain variable domain of VRC07 (SEQ ID NO: 2) and the light chain includes the light chain variable domain of VRC01 (SEQ ID NO: 9).
  • Cytotoxicity The toxicity of a molecule, such as an immunotoxin, to the cells intended to be targeted, as opposed to the cells of the rest of an organism.
  • toxicity refers to toxicity of an immunotoxin to cells other than those that are the cells intended to be targeted by the targeting moiety of the immunotoxin
  • animal toxicity refers to toxicity of the immunotoxin to an animal by toxicity of the immunotoxin to cells other than those intended to be targeted by the immunotoxin.
  • Detectable marker A detectable molecule (also known as a label) that is conjugated directly or indirectly to a second molecule, such as an antibody, to facilitate detection of the second molecule.
  • the detectable marker can be capable of detection by ELISA, spectrophotometry, flow cytometry, microscopy or diagnostic imaging techniques (such as CT scans, MRIs, ultrasound, fiberoptic examination, and laparoscopic examination).
  • detectable markers include fluorophores, fluorescent proteins, chemiluminescent agents, enzymatic linkages, radioactive isotopes and heavy metals or compounds (for example super paramagnetic iron oxide nanocrystals for detection by MRI).
  • a “labeled antibody” refers to incorporation of another molecule in the antibody.
  • the label is a detectable marker, such as the incorporation of a radiolabeled amino acid or attachment to a polypeptide of biotinyl moieties that can be detected by marked avidin (for example, streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods).
  • marked avidin for example, streptavidin containing a fluorescent marker or enzymatic activity that can be detected by optical or colorimetric methods.
  • Various methods of labeling polypeptides and glycoproteins are known in the art and may be used.
  • labels for polypeptides include, but are not limited to, the following: radioisotopes or radionuclides (such as 35 S or 131 I) fluorescent labels (such as fluorescein isothiocyanate (FITC), rhodamine, lanthanide phosphors), enzymatic labels (such as horseradish peroxidase, beta-galactosidase, luciferase, alkaline phosphatase), chemiluminescent markers, biotinyl groups, predetermined polypeptide epitopes recognized by a secondary reporter (such as a leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags), or magnetic agents, such as gadolinium chelates.
  • radioisotopes or radionuclides such as 35 S or 131 I
  • fluorescent labels such as fluorescein isothiocyanate (FITC), rhodamine, lanthanide phosphors
  • enzymatic labels
  • labels are attached by spacer arms of various lengths to reduce potential steric hindrance.
  • Methods for using detectable markers and guidance in the choice of detectable markers appropriate for various purposes are discussed for example in Sambrook et al. (Molecular Cloning: A Laboratory Manual, Cold Spring Harbor, N.Y., 1989) and Ausubel et al. (In Current Protocols in Molecular Biology, John Wiley & Sons, New York, 1998).
  • Detecting To identify the existence, presence, or fact of something. General methods of detecting are known to the skilled artisan and may be supplemented with the protocols and reagents disclosed herein. For example, included herein are methods of detecting a cell that expresses gp120 in a subject.
  • DNA sequencing The process of determining the nucleotide order of a given DNA molecule.
  • the general characteristics of “deep sequencing” are that genetic material is amplified, such as by polymerase chain reaction, and then the amplified products are ligated to a solid surface.
  • the sequence of the amplified target genetic material is then performed in parallel and the sequence information is captured by a computer.
  • the sequencing can be performed using automated Sanger sequencing (AB13730x1 genome analyzer), pyrosequencing on a solid support (454 sequencing, Roche), sequencing-by-synthesis with reversible terminations (ILLUMINA® Genome Analyzer), sequencing-by-ligation (ABI SOLiD®) or sequencing-by-synthesis with virtual terminators (HELISCOPE®).
  • DNA sequencing is performed using a chain termination method developed by Frederick Sanger, and thus termed “Sanger based sequencing” or “SBS.”
  • SBS serum based sequencing
  • This technique uses sequence-specific termination of a DNA synthesis reaction using modified nucleotide substrates. Extension is initiated at a specific site on the template DNA by using a short oligonucleotide primer complementary to the template at that region.
  • the oligonucleotide primer is extended using DNA polymerase in the presence of the four deoxynucleotide bases (DNA building blocks), along with a low concentration of a chain terminating nucleotide (most commonly a di-deoxynucleotide).
  • “Pyrosequencing” is an array based method, which has been commercialized by 454 Life Sciences (Branford, Conn.). In some embodiments of the array-based methods, single-stranded DNA is annealed to beads and amplified via EmPCR®. These DNA-bound beads are then placed into wells on a fiber-optic chip along with enzymes that produce light in the presence of ATP. When free nucleotides are washed over this chip, light is produced as the PCR amplification occurs and ATP is generated when nucleotides join with their complementary base pairs. Addition of one (or more) nucleotide(s) results in a reaction that generates a light signal that is recorded, such as by the charge coupled device (CCD) camera, within the instrument. The signal strength is proportional to the number of nucleotides, for example, homopolymer stretches, incorporated in a single nucleotide flow.
  • CCD charge coupled device
  • Effector molecule The portion of a chimeric molecule that is intended to have a desired effect on a cell or protein to which the chimeric molecule is targeted. Effector molecule is also known as an effector moiety, therapeutic agent, or diagnostic agent, or similar terms.
  • Epitope An antigenic determinant. These are particular chemical groups or peptide sequences on a molecule that are antigenic, i.e. that elicit a specific immune response.
  • An antibody specifically binds a particular antigenic epitope on a polypeptide. In some examples a disclosed antibody specifically binds to an epitope on the surface of gp120 from HIV.
  • Epitope Scaffold Refers to a heterologous protein that is engrafted with a foreign epitope of interest on its surface. Transplantation of the epitope is performed computationally in a manner that preserves its relevant structure and conformation. Mutations within the acceptor scaffold are made in order to accommodate the epitope graft. The graft can be modified to represent the sequences of different clades and strains.
  • Fc polypeptide The polypeptide including the constant region of an antibody excluding the first constant region immunoglobulin domain.
  • Fc region generally refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, and the last three constant region immunoglobulin domains of IgE and IgM.
  • An Fc region may also include part or all of the flexible hinge N-terminal to these domains.
  • an Fc region may or may not include the tailpiece, and may or may not be bound by the J chain.
  • the Fc region includes immunoglobulin domains Cgamma2 and Cgamma3 (C ⁇ 2 and C ⁇ 3) and the lower part of the hinge between Cgamma1 (C ⁇ 1) and C ⁇ 2.
  • the human IgG heavy chain Fc region is usually defined to include residues C226 or P230 to its carboxyl-terminus, wherein the numbering is according to the EU index as in Kabat.
  • the Fc region includes immunoglobulin domains Calpha2 and Calpha3 (C ⁇ 2 and C ⁇ 3) and the lower part of the hinge between Calpha1 (C ⁇ 1) and C ⁇ 2. Encompassed within the definition of the Fc region are functionally equivalent analogs and variants of the Fc region.
  • a functionally equivalent analog of the Fc region may be a variant Fc region, including one or more amino acid modifications relative to the wild-type or naturally existing Fc region.
  • Variant Fc regions will possess at least 50% homology with a naturally existing Fc region, such as about 80%, and about 90%, or at least about 95% homology.
  • Functionally equivalent analogs of the Fc region may include one or more amino acid residues added to or deleted from the N- or C-termini of the protein, such as no more than 30 or no more than 10 additions and/or deletions.
  • Functionally equivalent analogs of the Fc region include Fc regions operably linked to a fusion partner.
  • Fc region must include the majority of all of the Ig domains that compose Fc region as defined above; for example IgG and IgA Fc regions as defined herein must include the majority of the sequence encoding CH 2 and the majority of the sequence encoding CH 3 . Thus, the CH 2 domain on its own, or the CH 3 domain on its own, are not considered Fc region.
  • the Fc region may refer to this region in isolation, or this region in the context of an Fc fusion polypeptide (immunoadhesin, see below).
  • Framework Region Amino acid sequences interposed between CDRs. Includes variable light and variable heavy framework regions. The framework regions serve to hold the CDRs in an appropriate orientation for antigen binding.
  • gp120 An envelope protein from Human Immunodeficiency Virus (HIV). This envelope protein is initially synthesized as a longer precursor protein of 845-870 amino acids in size, designated gp160. gp160 is cleaved by a cellular protease into gp120 and gp41. gp120 contains most of the external, surface-exposed, domains of the HIV envelope glycoprotein complex, and it is gp120 which binds both to cellular CD4 receptors and to cellular chemokine receptors (such as CCR5).
  • HIV Human Immunodeficiency Virus
  • the mature gp120 wildtype polypeptides have about 500 amino acids in the primary sequence. gp120 is heavily N-glycosylated giving rise to an apparent molecular weight of 120 kD.
  • the polypeptide is comprised of five conserved regions (C1-C5) and five regions of high variability (V1-V5).
  • Exemplary sequence of wt gp120 polypeptides are shown on GENBANK®, for example accession numbers AAB05604 and AAD12142 (as available on Oct. 16, 2009), incorporated by reference herein. It is understood that there are numerous variation in the sequence of gp120 from what is given in GENBANK®, for example accession numbers AAB05604 and AAD12142, and that these variants are skill recognized in the art as gp120.
  • the gp120 core has a molecular structure, which includes two domains: an “inner” domain (which faces gp41) and an “outer” domain (which is mostly exposed on the surface of the oligomeric envelope glycoprotein complex).
  • the two gp120 domains are separated by a “bridging sheet” that is not part of either domain.
  • the gp120 core includes 25 beta strands, 5 alpha helices, and 10 defined loop segments.
  • the third variable domain referred to herein as the V3 loop is a loop of about 35 amino acids critical for the binding of the co-receptor and determination of which of the co-receptors will bind.
  • the V3 loop includes residues 296-331.
  • HIV Envelope protein The HIV envelope protein is initially synthesized as a longer precursor protein of 845-870 amino acids in size, designated gp160. gp160 forms a homotrimer and undergoes glycosylation within the Golgi apparatus. In vivo, it is then cleaved by a cellular protease into gp120 and gp41. gp120 contains most of the external, surface-exposed, domains of the HIV envelope glycoprotein complex, and it is gp120 which binds both to cellular CD4 receptors and to cellular chemokine receptors (such as CCR5). gp41 contains a transmembrane domain and remains in a trimeric configuration; it interacts with gp120 in a non-covalent manner.
  • Host cells Cells in which a vector can be propagated and its DNA expressed, for example a disclosed antibody can be expressed in a host cell.
  • the cell may be prokaryotic or eukaryotic.
  • the term also includes any progeny of the subject host cell. It is understood that all progeny may not be identical to the parental cell since there may be mutations that occur during replication. However, such progeny are included when the term “host cell” is used.
  • HIV Human Immunodeficiency Virus
  • HIV disease A retrovirus that causes immunosuppression in humans (HIV disease), and leads to a disease complex known as the acquired immunodeficiency syndrome (AIDS).
  • HIV disease refers to a well-recognized constellation of signs and symptoms (including the development of opportunistic infections) in persons who are infected by an HIV virus, as determined by antibody or western blot studies. Laboratory findings associated with this disease include a progressive decline in T cells. HIV includes HIV type 1 (HIV-1) and HIV type 2 (HIV-2).
  • Related viruses that are used as animal models include simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV). Treatment of HIV-1 with HAART has been effective in reducing the viral burden and ameliorating the effects of HIV-1 infection in infected individuals.
  • HXB2 numbering system A reference numbering system for HIV protein and nucleic acid sequences, using HIV-1 HXB2 strain sequences as a reference for all other HIV strain sequences.
  • the person of ordinary skill in the art is familiar with the HXB2 numbering system, and this system is set forth in “Numbering Positions in HIV Relative to HXB2CG,” Bette Korber et al., Human Retroviruses and AIDS 1998: A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Korber B, Kuiken C L, Foley B, Hahn B, McCutchan F, Mellors J W, and Sodroski J, Eds.
  • HXB2 is also known as: HXBc2, for HXB clone 2; HXB2R, in the Los Alamos HIV database, with the R for revised, as it was slightly revised relative to the original HXB2 sequence; and HXB2CG in GENBANKTM, for HXB2 complete genome.
  • the numbering used in gp120 polypeptides disclosed herein is relative to the HXB2 numbering scheme.
  • IgA A polypeptide belonging to the class of antibodies that are substantially encoded by a recognized immunoglobulin alpha gene. In humans, this class or isotype includes IgA 1 and IgA 2 .
  • IgA antibodies can exist as monomers, polymers (referred to as pIgA) of predominantly dimeric form, and secretory IgA.
  • the constant chain of wild-type IgA contains an 18-amino-acid extension at its C-terminus called the tail piece (tp).
  • Polymeric IgA is secreted by plasma cells with a 15-kDa peptide called the J chain linking two monomers of IgA through the conserved cysteine residue in the tail piece.
  • IgG A polypeptide belonging to the class or isotype of antibodies that are substantially encoded by a recognized immunoglobulin gamma gene. In humans, this class includes IgG 1 , IgG 2 , IgG 3 , and IgG 4 . In mice, this class includes IgG 1 , IgG 2a , IgG 2b , IgG 3 .
  • Immune complex The binding of antibody to a soluble antigen forms an immune complex.
  • the formation of an immune complex can be detected through conventional methods known to the skilled artisan, for instance immunohistochemistry, immunoprecipitation, flow cytometry, immunofluorescence microscopy, ELISA, immunoblotting (for example, Western blot), magnetic resonance imaging, CT scans, X-ray and affinity chromatography. Immunological binding properties of selected antibodies may be quantified using methods well known in the art.
  • Immunoadhesin A molecular fusion of a protein with the Fc region of an immunoglobulin, wherein the immunoglobulin retains specific properties, such as Fc receptor binding and increased half-life.
  • An Fc fusion combines the Fc region of an immunoglobulin with a fusion partner, which in general can be any protein, polypeptide, peptide, or small molecule.
  • immunoadhesin includes the hinge, CH 2 , and CH 3 domains of the immunoglobulin gamma 1 heavy chain constant region.
  • the immunoadhesin includes the CH 2 , and CH 3 domains of an IgG.
  • Immunogen A compound, composition, or substance (for example, a protein or a portion thereof) that is capable of inducing an immune response in a mammal, such as a mammal infected or at risk of infection with a pathogen.
  • Administration of an immunogen can lead to protective immunity and/or proactive immunity against a pathogen of interest.
  • an immunogen is an HIV antigen.
  • immunogens include, but are not limited to, peptides, lipids, polysaccharides, combinations thereof, and nucleic acids containing antigenic determinants, such as those recognized by an immune cell.
  • immunogens include peptides derived from a pathogen of interest. Exemplary pathogens include bacteria, fungi, viruses and parasites.
  • an immunogen is derived from HIV, such as a gp120 polypeptide derived from HIV or antigenic fragment thereof.
  • Immunological Probe A molecule that can be used for selection of antibodies from sera which are directed against a specific epitope, including from human patient sera.
  • the epitope scaffolds, along with related point mutants, can be used as immunological probes in both positive and negative selection of antibodies against the epitope graft.
  • immunological probes are engineered variants of gp120.
  • Immunologically reactive conditions Includes reference to conditions which allow an antibody raised against a particular epitope to bind to that epitope to a detectably greater degree than, and/or to the substantial exclusion of, binding to substantially all other epitopes. Immunologically reactive conditions are dependent upon the format of the antibody binding reaction and typically are those utilized in immunoassay protocols or those conditions encountered in vivo. See Harlow & Lane, supra, for a description of immunoassay formats and conditions. The immunologically reactive conditions employed in the methods are “physiological conditions” which include reference to conditions (e.g., temperature, osmolarity, pH) that are typical inside a living mammal or a mammalian cell.
  • the intra-organismal and intracellular environment normally lies around pH 7 (e.g., from pH 6.0 to pH 8.0, more typically pH 6.5 to 7.5), contains water as the predominant solvent, and exists at a temperature above 0° C. and below 50° C. Osmolarity is within the range that is supportive of cell viability and proliferation.
  • Inhibiting or treating a disease Inhibiting the full development of a disease or condition, for example, in a subject who is at risk for a disease such as acquired immunodeficiency syndrome (AIDS). “Treatment” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. The term “ameliorating,” with reference to a disease or pathological condition, refers to any observable beneficial effect of the treatment.
  • AIDS acquired immunodeficiency syndrome
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the viral load, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • a “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs for the purpose of decreasing the risk of developing pathology.
  • Isolated An “isolated” biological component (such as a cell, for example a B cell, a nucleic acid, peptide, protein or antibody) has been substantially separated, produced apart from, or purified away from other biological components in the cell of the organism in which the component naturally occurs, such as, other chromosomal and extrachromosomal DNA and RNA, and proteins. Nucleic acids, peptides and proteins which have been “isolated” thus include nucleic acids and proteins purified by standard purification methods. The term also embraces nucleic acids, peptides, and proteins prepared by recombinant expression in a host cell as well as chemically synthesized nucleic acids.
  • an antibody such as an antibody specific for gp120 can be isolated, for example isolated from a subject infected with HIV.
  • K d The dissociation constant for a given interaction, such as a polypeptide ligand interaction or an antibody antigen interaction.
  • a polypeptide ligand interaction such as a polypeptide ligand interaction or an antibody antigen interaction.
  • an antibody such as VRC07 or variant thereof as disclosed herein
  • an antigen such as gp120
  • Label A detectable compound or composition that is conjugated directly or indirectly to another molecule, such as an antibody or a protein, to facilitate detection of that molecule.
  • molecule such as an antibody or a protein
  • labels include fluorescent tags, enzymatic linkages, and radioactive isotopes.
  • a disclosed antibody is labeled.
  • Linker A bi-functional molecule that can be used to link two molecules into one contiguous molecule, for example, to link an effector molecule to an antibody.
  • a conjugate includes a linker between the effector molecule or detectable marker and an antibody.
  • the linker is cleavable under intracellular conditions, such that cleavage of the linker releases the effector molecule or detectable marker from the antibody in the intracellular environment.
  • the linker is not cleavable and the effector molecule or detectable marker can be released, for example, by antibody degradation.
  • a linker is a peptide within an antibody binding fragment (such as an Fv fragment) which serves to indirectly bond the variable heavy chain to the variable light chain.
  • conjugating refers to making two polypeptides into one contiguous polypeptide molecule, to covalently attaching a radionuclide or other molecule to a polypeptide, such as an antibody that specifically binds gp120, or an antibody binding fragment thereof.
  • a polypeptide such as an antibody that specifically binds gp120, or an antibody binding fragment thereof.
  • the terms include reference to joining a ligand, such as an antibody moiety, to an effector molecule.
  • the linkage can be either by chemical or recombinant means.
  • “Chemical means” refers to a reaction between the antibody moiety and the effector molecule such that there is a covalent bond formed between the two molecules to form one molecule.
  • Neutralizing antibody An antibody which reduces the infectious titer of an infectious agent by binding to a specific antigen on the infectious agent.
  • the infectious agent is a virus.
  • an antibody that is specific for gp120 neutralizes the infectious titer of HIV.
  • a “broadly neutralizing antibody” is an antibody that binds to and inhibits the function of related antigens, such as antigens that share at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identity with antigenic surface of the antigen.
  • the antibody can bind to and inhibit the function of an antigen from more than one class and/or subclass of the pathogen.
  • the antibody can bind to and inhibit the function of an antigen, such as gp120 from more than one Glade.
  • an antigen such as gp120 from more than one Glade.
  • broadly neutralizing antibodies to HIV are distinct from other antibodies to HIV in that they neutralize a high percentage of the many types of HIV in circulation.
  • Nucleic acid A polymer composed of nucleotide units (ribonucleotides, deoxyribonucleotides, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof) linked via phosphodiester bonds, related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof.
  • nucleotide polymers in which the nucleotides and the linkages between them include non-naturally occurring synthetic analogs, such as, for example and without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs), and the like.
  • oligonucleotide typically refers to short polynucleotides, generally no greater than about 50 nucleotides. It will be understood that when a nucleotide sequence is represented by a DNA sequence (i.e., A, T, G, C), this also includes an RNA sequence (i.e., A, U, G, C) in which “U” replaces “T.”
  • nucleotide sequences the left-hand end of a single-stranded nucleotide sequence is the 5′-end; the left-hand direction of a double-stranded nucleotide sequence is referred to as the 5′-direction.
  • the direction of 5′ to 3′ addition of nucleotides to nascent RNA transcripts is referred to as the transcription direction.
  • the DNA strand having the same sequence as an mRNA is referred to as the “coding strand;” sequences on the DNA strand having the same sequence as an mRNA transcribed from that DNA and which are located 5′ to the 5′-end of the RNA transcript are referred to as “upstream sequences;” sequences on the DNA strand having the same sequence as the RNA and which are 3′ to the 3′ end of the coding RNA transcript are referred to as “downstream sequences.”
  • cDNA refers to a DNA that is complementary or identical to an mRNA, in either single stranded or double stranded form.
  • Encoding refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom.
  • a gene encodes a protein if transcription and translation of mRNA produced by that gene produces the protein in a cell or other biological system.
  • coding strand the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings
  • non-coding strand used as the template for transcription
  • a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA may include introns.
  • Recombinant nucleic acid refers to a nucleic acid having nucleotide sequences that are not naturally joined together. his includes nucleic acid vectors including an amplified or assembled nucleic acid which can be used to transform a suitable host cell.
  • a host cell that includes the recombinant nucleic acid is referred to as a “recombinant host cell.” The gene is then expressed in the recombinant host cell to produce, e.g., a “recombinant polypeptide.”
  • a recombinant nucleic acid may serve a non-coding function (e.g., promoter, origin of replication, ribosome-binding site, etc.) as well.
  • a first sequence is an “antisense” with respect to a second sequence if a polynucleotide whose sequence is the first sequence specifically hybridizes with a polynucleotide whose sequence is the second sequence.
  • sequence relationships between two or more nucleotide sequences or amino acid sequences include “reference sequence,” “selected from,” “comparison window,” “identical,” “percentage of sequence identity,” “substantially identical,” “complementary,” and “substantially complementary.”
  • sequence comparison For sequence comparison of nucleic acid sequences, typically one sequence acts as a reference sequence, to which test sequences are compared.
  • test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters are used.
  • Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith & Waterman, Adv. Appl. Math. 2:482, 1981, by the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443, 1970, by the search for similarity method of Pearson & Lipman, Proc. Nat'l.
  • PILEUP uses a simplification of the progressive alignment method of Feng & Doolittle, J. Mol. Evol. 35:351-360, 1987. The method used is similar to the method described by Higgins & Sharp, CABIOS 5:151-153, 1989.
  • a reference sequence is compared to other test sequences to determine the percent sequence identity relationship using the following parameters: default gap weight (3.00), default gap length weight (0.10), and weighted end gaps.
  • PILEUP can be obtained from the GCG sequence analysis software package, e.g., version 7.0 (Devereaux et al., Nuc. Acids Res. 12:387-395, 1984.
  • BLAST Altschul et al., J. Mol. Biol. 215:403-410, 1990 and Altschul et al., Nucleic Acids Res. 25:3389-3402, 1977.
  • Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov).
  • oligonucleotide is a linear polynucleotide sequence of up to about 100 nucleotide bases in length.
  • a polynucleotide or nucleic acid sequence refers to a polymeric form of nucleotide at least 10 bases in length.
  • a recombinant polynucleotide includes a polynucleotide that is not immediately contiguous with both of the coding sequences with which it is immediately contiguous (one on the 5′ end and one on the 3′ end) in the naturally occurring genome of the organism from which it is derived.
  • the term therefore includes, for example, a recombinant DNA which is incorporated into a vector; into an autonomously replicating plasmid or virus; or into the genomic DNA of a prokaryote or eukaryote, or which exists as a separate molecule (e.g., a cDNA) independent of other sequences.
  • the nucleotides can be ribonucleotides, deoxyribonucleotides, or modified forms of either nucleotide.
  • the term includes single- and double-stranded forms of DNA.
  • a gp120 polynucleotide is a nucleic acid encoding a gp120 polypeptide.
  • a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence.
  • a promoter such as the CMV promoter
  • operably linked DNA sequences are contiguous and, where necessary to join two protein-coding regions, in the same reading frame.
  • compositions and formulations suitable for pharmaceutical delivery of the disclosed antibodies are conventional. Remington's Pharmaceutical Sciences , by E. W. Martin, Mack Publishing Co., Easton, Pa., 19th Edition, 1995, describes compositions and formulations suitable for pharmaceutical delivery of the disclosed antibodies.
  • parenteral formulations usually include injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • injectable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • solid compositions e.g., powder, pill, tablet, or capsule forms
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • Pharmaceutical agent A chemical compound or composition capable of inducing a desired therapeutic or prophylactic effect when properly administered to a subject or a cell.
  • a pharmaceutical agent includes one or more of the disclosed antibodies.
  • Polypeptide Any chain of amino acids, regardless of length or post-translational modification (e.g., glycosylation or phosphorylation).
  • the polypeptide is gp120 polypeptide.
  • the polypeptide is a disclosed antibody or a fragment thereof.
  • a “residue” refers to an amino acid or amino acid mimetic incorporated in a polypeptide by an amide bond or amide bond mimetic.
  • a polypeptide has an amino terminal (N-terminal) end and a carboxy-terminal end.
  • a promoter is an array of nucleic acid control sequences that directs transcription of a nucleic acid.
  • a promoter includes necessary nucleic acid sequences near the start site of transcription, for example, in the case of a polymerase II type promoter, a TATA element.
  • a promoter also optionally includes distal enhancer or repressor elements which can be located as much as several thousand base pairs from the start site of transcription. Both constitutive and inducible promoters are included (see for example, Bitter et al., Methods in Enzymology 153:516-544, 1987).
  • promoters include promoters derived from the genome of mammalian cells (such as the metallothionein promoter) or from mammalian viruses (such as the retrovirus long terminal repeat; the adenovirus late promoter; the vaccinia virus 7.5K promoter) may be used. Promoters produced by recombinant DNA or synthetic techniques may also be used.
  • a polynucleotide can be inserted into an expression vector that contains a promoter sequence which facilitates the efficient transcription of the inserted genetic sequence of the host.
  • the expression vector typically contains an origin of replication, a promoter, as well as specific nucleic acid sequences that allow phenotypic selection of the transformed cells.
  • purified does not require absolute purity; rather, it is intended as a relative term.
  • a purified peptide preparation is one in which the peptide or protein (such as an antibody) is more enriched than the peptide or protein is in its natural environment within a cell.
  • a preparation is purified such that the protein or peptide represents at least 50% of the total peptide or protein content of the preparation.
  • a recombinant nucleic acid is one that has a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two otherwise separated segments of sequence. This artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques.
  • Sequence identity The similarity between amino acid sequences is expressed in terms of the similarity between the sequences, otherwise referred to as sequence identity. Sequence identity is frequently measured in terms of percentage identity (or similarity or homology); the higher the percentage, the more similar the two sequences are. Homologs or variants of a polypeptide will possess a relatively high degree of sequence identity when aligned using standard methods.
  • NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al., J. Mol. Biol. 215:403, 1990) is available from several sources, including the National Center for Biotechnology Information (NCBI, Bethesda, Md.) and on the internet, for use in connection with the sequence analysis programs blastp, blastn, blastx, tblastn and tblastx. A description of how to determine sequence identity using this program is available on the NCBI website on the internet.
  • Homologs and variants of a V L or a V H of an antibody that specifically binds a polypeptide are typically characterized by possession of at least about 75%, for example at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity counted over the full length alignment with the amino acid sequence of interest. Proteins with even greater similarity to the reference sequences will show increasing percentage identities when assessed by this method, such as at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.
  • homologs and variants When less than the entire sequence is being compared for sequence identity, homologs and variants will typically possess at least 80% sequence identity over short windows of 10-20 amino acids, and may possess sequence identities of at least 85% or at least 90% or 95% depending on their similarity to the reference sequence. Methods for determining sequence identity over such short windows are available at the NCBI website on the internet. One of skill in the art will appreciate that these sequence identity ranges are provided for guidance only; it is entirely possible that strongly significant homologs could be obtained that fall outside of the ranges provided.
  • an antibody refers to a binding reaction which determines the presence of a target protein, peptide, or polysaccharide in the presence of a heterogeneous population of proteins and other biologics.
  • an antibody binds preferentially to a particular target protein, peptide or polysaccharide (such as an antigen present on the surface of a pathogen, for example gp120) and does not bind in a significant amount to other proteins or polysaccharides present in the sample or subject.
  • Specific binding can be determined by methods known in the art.
  • specific binding of the antigen and antibody has a K d of less than about 10 ⁇ 6 Molar, such as less than about 10 ⁇ 6 Molar, 10 ⁇ 7 Molar, 10 ⁇ 8 Molar, 10 ⁇ 9 , or even less than about 10 ⁇ 10 Molar.
  • T Cell A white blood cell critical to the immune response.
  • T cells include, but are not limited to, CD4 + T cells and CD8 + T cells.
  • a CD4 + T lymphocyte is an immune cell that carries a marker on its surface known as “cluster of differentiation 4” (CD4). These cells, also known as helper T cells, help orchestrate the immune response, including antibody responses as well as killer T cell responses.
  • CD8 + T cells carry the “cluster of differentiation 8” (CD8) marker.
  • a CD8 T cells is a cytotoxic T lymphocytes.
  • a CD8 cell is a suppressor T cell.
  • Therapeutic agent Used in a generic sense, it includes treating agents, prophylactic agents, and replacement agents.
  • a therapeutic agent is used to ameliorate a specific set of conditions in a subject with a disease or a disorder.
  • Therapeutically effective amount A quantity of a specific substance, such as a disclosed antibody, sufficient to achieve a desired effect in a subject being treated. For instance, this can be the amount necessary to inhibit HIV replication or treat HIV infection. In several embodiments, a therapeutically effective amount is the amount necessary to reduce a sign or symptom of HIV infection, and/or to decrease viral titer in a subject. When administered to a subject, a dosage will generally be used that will achieve target tissue concentrations that has been shown to achieve a desired in vitro effect.
  • Toxin An effector molecule that induces cytotoxicity when it contacts a cell.
  • toxins include, but are not limited to, abrin, ricin, auristatins (such as monomethyl auristatin E (MMAE; see for example, Francisco et al., Blood, 102: 1458-1465, 2003)) and monomethyl auristatin F (MMAF; see, for example, Doronina et al., BioConjugate Chem., 17: 114-124, 2006), maytansinoids (such as DM1; see, for example, Phillips et al., Cancer Res., 68:9280-9290, 2008), Pseudomonas exotoxin (PE, such as PE35, PE37, PE38, and PE40), diphtheria toxin (DT), botulinum toxin, saporin, restrictocin or gelonin, or modified toxins thereof, or other toxic agents that directly or indirectly inhibit cell growth
  • PE Ps
  • PE and DT are highly toxic compounds that typically bring about death through liver toxicity.
  • PE and DT can be modified into a form for use as an immunotoxin by removing the native targeting component of the toxin (such as the domain Ia of PE and the B chain of DT) and replacing it with a different targeting moiety, such as an antibody.
  • a phrase that is used to describe any environment that permits a desired activity is formation of an immune complex.
  • the desired activity is treatment of HIV infection.
  • a nucleic acid molecule as introduced into a host cell, thereby producing a transformed host cell.
  • a vector may include nucleic acid sequences that permit it to replicate in a host cell, such as an origin of replication.
  • a vector may also include one or more selectable marker genes and other genetic elements known in the art.
  • Virus Microscopic infectious organism that reproduces inside living cells.
  • a virus consists essentially of a core of a single nucleic acid surrounded by a protein coat, and has the ability to replicate only inside a living cell. “Viral replication” is the production of additional virus by the occurrence of at least one viral life cycle. A virus may subvert the host cells' normal functions, causing the cell to behave in a manner determined by the virus. For example, a viral infection may result in a cell producing a cytokine, or responding to a cytokine, when the uninfected cell does not normally do so.
  • RNA viruses wherein the viral genome is RNA.
  • the genomic RNA is reverse transcribed into a DNA intermediate which is integrated very efficiently into the chromosomal DNA of infected cells.
  • the integrated DNA intermediate is referred to as a provirus.
  • the term “lentivirus” is used in its conventional sense to describe a genus of viruses containing reverse transcriptase.
  • the lentiviruses include the “immunodeficiency viruses” which include human immunodeficiency virus (HIV) type 1 and type 2 (HIV-I and HIV-II), simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV).
  • VRC01 A monoclonal antibody that specifically binds to gp120 and is neutralizes a broad range of HIV viruses, wherein the sequences of the heavy and light chain variable domains of VRC01 are set forth herein as SEQ ID NO: 5 and SEQ ID NO: 9, respectively. See also, Wu et al., Science, 329(5993):856-861, 2010, and PCT publication WO2012/154312, incorporated by reference herein in its entirety.
  • VRC01-like antibody, heavy chain or light chain A VRC01-like antibody or a heavy chain or light chain that can complement with a corresponding heavy chain or light chain from VRC01, as specifically defined herein.
  • VRC01-like antibodies, and methods for identifying and producing these antibodies are disclosed herein. Generally, these antibodies bind to the CD4 binding surface of gp120 in substantially the same orientation as VRC01, and are broadly neutralizing VRC01-like antibodies mimic the binding of CD4 to gp120 with several of the important contacts between CD4 and gp120 mimicked by the VRC01-like antibodies.
  • a VRC07 or VRC07 variant heavy chain variable domain disclosed herein can be included on a heavy chain and cross-complemented with a light chain including a variable domain of a VRC01 like antibody, such as VRC-PG04, VRC-PG04b, VRC-CH30, VRC-CH31, VRC-CH32, VRC-CH33, VRC-CH34, VRC01, VRC02, VRC03, NIH4546, NIH4546 G54W, 3BNC60, 3BNC117, 12A12, 12A21, 1NC9, 1B2530, 8ANC131 or 8ANC134, and maintain high binding affinity for gp120.
  • VRC01 like antibody such as VRC-PG04, VRC-PG04b, VRC-CH30, VRC-CH31, VRC-CH32, VRC-CH33, VRC-CH34, VRC01, VRC02, VRC03, NIH4546, NIH4546 G54W, 3BNC60, 3BNC117
  • a VRC01 variant light chain variable domain disclosed herein can be included on a light chain and cross-complemented with a heavy chain including a variable domain of a VRC01 like antibody, such as VRC-PG04, VRC-PG04b, VRC-CH30, VRC-CH31, VRC-CH32, VRC-CH33, VRC-CH34, VRC01, VRC02, VRC03, NIH4546, NIH4546 G54W, 3BNC60, 3BNC117, 12A12, 12A21, 1NC9, 1B2530, 8ANC131 or 8ANC134, and maintain high binding affinity for gp120.
  • VRC01 like antibody such as VRC-PG04, VRC-PG04b, VRC-CH30, VRC-CH31, VRC-CH32, VRC-CH33, VRC-CH34, VRC01, VRC02, VRC03, NIH4546, NIH4546 G54W, 3BNC60, 3BNC117, 12A12
  • VRC01-like antibodies including:
  • VRC01-like antibodies, heavy chains and light chains disclosed in PCT International Application No. PCT/US2010/050295, filed Sep. 24, 2010, which is incorporated by reference herein and Wu et al., “Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1,” Science, 329(5993):856-861, 2010, which is incorporated by reference herein.
  • VRC01-like antibodies, heavy chains and light chains disclosed in Scheid et al., “Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding,” Science, 333(6049):1633-1637, 2011, incorporated by reference herein.
  • These include the heavy and light chains of the 3BNC117, 3BNC60, 12A12, 12A21, NIH4546, 8ANC131, 8ANC134, 1B2530, 1NC9 antibodies (corresponding Accession Nos. shown in Table 1, below, and disclosed in WIPO Pub. No.
  • VRC01-like antibodies, heavy chains and light chains disclosed in Wu et al., “Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing,” Science, 333(6049):1593-1602, 2011, incorporated herein by reference.
  • These certain VRC01-like antibodies, heavy chains and light chains include the heavy and light chains of the VRC-PG04 and VRC-PG04b antibodies (GENBANK® Accession Nos. JN159464 to JN159467, respectively), VRC-CH 30 , VRC-CH31, and VRC-CH32 antibodies (GENBANK® Accession Nos. JN159434 to JN159439, respectively), and VRC-CH33 and VRC-CH34 antibodies (GENBANK® Accession Nos.
  • VRC01-like antibodies, heavy chains and light chains also include 24 heavy chains from donor 74, 2008 (GENBANK® Accession Nos. JN159440 to JN159463), two heavy chains from donor 45, 2008 (GENBANK® Accession Nos. JN159474 and JN159475) and two light chains from donor 45, 2001 (GENBANK® Accession Nos. JN159468 and JN159469).
  • These certain VRC01-like antibodies, heavy chains and light chains also include 1561 unique sequences associated with neutralizing CDR H3 distributions with at least one low divergent member shown in FIG. 6B and FIG. S16 of Wu et al., Science, 333(6049):1593-1602, 2011 (GENBANK® Accession Nos. JN157873 to JN159433, respectively).
  • These include the heavy and light chains of the NIH4546 antibody with a G54W amino acid substitution (Kabat numbering) in the heavy chain variable domain.
  • HE584540 EMBL Acc. No. HE584550 8ANC134 EMBL Acc. No. HE584551 EMBL Acc. No. HE584552 1B2530 EMBL Acc. No. HE584545 EMBL Acc. No. HE584546 1NC9 EMBL Acc. No. HE584547 EMBL Acc. No. HE584548 II. Description of Several Embodiments
  • Isolated monoclonal antibodies that specifically bind gp120 are disclosed herein.
  • the antibodies can be fully human.
  • compositions including these monoclonal antibodies and a pharmaceutically acceptable carrier are also provided.
  • Nucleic acids encoding these antibodies, expression vectors including these nucleic acids, and isolated host cells that express the nucleic acids are also provided.
  • compositions including the monoclonal antibodies specific for gp120 can be used for research, diagnostic and therapeutic purposes.
  • the monoclonal antibodies disclosed herein can be used to diagnose or treat a subject having an HIV-1 infection and/or AIDS.
  • the antibodies can be used to determine HIV-1 titer in a subject.
  • the antibodies disclosed herein also can be used to study the biology of the human immunodeficiency virus.
  • monoclonal antibodies refers to isolated monoclonal antibodies that include heavy and light chain variable domains including a CDR1, CDR2 and CDR3 with reference to the IMGT or Kabat numbering scheme (unless the context indicates otherwise).
  • CDR numbering schemes such as the Kabat, Chothia or IMGT numbering schemes
  • VRC07 monoclonal antibody which specifically binds to the CD4 binding site of the gp120 protein of HIV, and is neutralizing VRC07 is a VRC01-like monoclonal antibody, and includes a novel heavy chain (“VRC07 heavy chain”) cross complemented with the light chain of the VRC01 monoclonal antibody.
  • VRC07 heavy chain is a clonal variant of the VRC01 heavy chain. As described in the Examples section, VRC07 has increased binding affinity for gp120, but does not have increased self-reactivity, compared to VRC01. Further disclosed herein are variants of the VRC07 heavy chain and the VRC01 light chain, and cross-complemented monoclonal antibodies including such variants that have increased binding affinity for gp120, but do not have increased self-reactivity compared to VRC01.
  • the CDR positions of the VRC07 monoclonal antibody heavy chain according to the Kabat and IMGT numbering schemes are shown in FIG. 8 .
  • the CDR positions of the VRC01 light chain variable domain according to the Kabat and IMGT numbering schemes are shown in FIG. 8 .
  • reference to particular amino acid substitutions in the heavy or light chains of the disclosed antibodies is made according to the Kabat numbering schemes.
  • the VRC07 heavy chain substitution G54H referenced herein refers to the Kabat numbering scheme.
  • Kabat position G54 of the VRC07 heavy chain variable domain corresponds to position 55 of the linear sequence of the VRC07 heavy chain variable domain (set forth as SEQ ID NO: 2).
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein heavy chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 2 (VRC07 heavy chain variable domain), and further includes one or more amino acid substitutions at Kabat positions I37, G54, S58, and T93.
  • SEQ ID NO: 40 is a consensus amino acid sequence of the heavy chain variable domain of VRC07 with amino acid substitutions at one, two, three, four, or none of positions I37, G54, S58, and T93 (Kabat numbering):
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the HCDR1, HCD2 and/or HCD3 of SEQ ID NO: 40, as defined using the Kabat or IMGT CDR positions wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the HCDR1, HCDR2 and HCDR3 of SEQ ID NO: 40, as defined using the Kabat or IMGT CDR positions wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the person of ordinary skill in the art is familiar with the Kabat and IMGT CDR positioning in an antibody variable domain sequence.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the HCDR1, HCD2 and/or HCD3 of SEQ ID NO: 2, as defined using the Kabat or IMGT CDR positions, and further includes a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 2, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 2, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 2, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kab
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the HCDR1, HCD2 and/or HCD3 of SEQ ID NO: 2, as defined using the Kabat or IMGT CDR positions, and further includes a G54H substitution, and further includes a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 2, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 2, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 2, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is G, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3 of SEQ ID NO: 40
  • X 2 is G
  • the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is H, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3 of SEQ ID NO: 40
  • X 2 is H
  • the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is S, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 31-35
  • CDR2 50-66
  • CDR3 99-114
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is S, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 31-35
  • CDR2 50-66
  • CDR3 99-114
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is N, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 31-35
  • CDR2 50-66
  • CDR3 99-114
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is N, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the amino acid sequence of SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is S and X 4 is T (VRC07 G54H; SEQ ID NO: 32), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the amino acid sequence of SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is N and X 4 is T (VRC07 G54H, S58N; SEQ ID NO: 258), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the amino acid sequence of SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is S and X 4 is A (VRC07 I37V, G54H, T93A; SEQ ID NO: 259), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the amino acid sequence of SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is N and X 4 is A (VRC07 I37V, G54H, S58N, T93A; SEQ ID NO: 260), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the disclosed heavy chain variable domains can be included on a heavy chain that is complemented with a VRC01 light chain or any of the VRC01 light chain variants disclosed herein (such as the antibody light chains described in the next section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the heavy chain can be complemented with the light chain of a known VRC01-like antibody (for example the light chain of VRC01 or NIH4546,) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing
  • the histidine substitution at Kabat position 54 of the VRC07 heavy chain variable domain disclosed herein can be included on other VRC01-like antibodies, to generate a monoclonal antibody with improved binding affinity of gp120, but which is not self-reactive and/or has low self-reactivity.
  • the histidine substitution at Kabat position 54 of can be included on the heavy chain variable domain of a VRC01-like antibody, to generate a monoclonal antibody with improved binding affinity of gp120, but which is not self-reactive and/or has low self-reactivity, for example, compared to the VRC01-like antibody in the absence of the histidine substitution at Kabat position 54.
  • an isolated VRC01-like monoclonal antibody wherein the antibody includes a VRC01-like heavy chain and a VRC01-like light chain, wherein the heavy chain further includes substitution of a histidine residue for the residue at position 54 (Kabat numbering) of the heavy chain, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the amino acid substitution is a G54H substitution.
  • Non-limiting examples of VRC01-like monoclonal antibody heavy chain variable domains that can be modified with the histidine substitution at Kabat position 54 include the heavy chain variable domains of the VRC01, VRC02, VRC03, NIH4546, VRC-PG04, VRC-PG04b, VRC-CH30, VRC-CH31, VRC-CH32, VRC-CH33, VRC-CH34, 3BNC60, 3BNC117, 12A12, 12A21, 1NC9, 1B2530, 8ANC131 or 8ANC134 monoclonal antibodies.
  • the sequence of accession numbers of the heavy chain variable domains of these antibodies are familiar to the person of ordinary skill in the art and provided herein.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 196 (NIH4546 heavy chain variable domain, IMGT CDRs), further including a glycine to histidine substitution at Kabat position 54 (a G54H substitution), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3
  • SEQ ID NO: 196 NIH4546 heavy chain variable domain, IMGT CDRs
  • a G54H substitution glycine to histidine substitution at Kabat position 54
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and 99-114 (CDR3) of SEQ ID NO: 196 (NIH4546 heavy chain variable domain, IMGT CDRs), further including a glycine to histidine substitution at Kabat position 54 (a G54H substitution), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 31-35
  • CDR2 50-66
  • CDR3 CDR3
  • SEQ ID NO: 196 NIH4546 heavy chain variable domain, IMGT CDRs
  • a G54H substitution glycine to histidine substitution at Kabat position 54
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 196, and further including a glycine to histidine substitution at Kabat position 54 (a G54H substitution), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • SEQ ID NO: 238 is a consensus amino acid sequence of a VRC01-like light chain variable domain with amino acid substitutions at one or more of positions E1, I2, V3, I20, S63, S65, W67, D70, N72, T74, F97, V106, and 1108 (Kabat numbering) compared to the light chain variable domain of
  • VRC01 X 1 X 2 X 3 LTQSPGTLSLSPGETAX 4 ISCRTSQYGSLAWYQQRPGQAPRLVIYSGSTRAAGIPDRF X 5 G X 6 R X 7 GP X 8 Y X 9 L X 10 ISNLESGDFGVYYCQQYE X 11 FGQGTKVQ X 12 D X 13 K (SEQ ID NO: 238), wherein X 1 is E or no amino acid; X 2 is I or no amino acid; X 3 is V, E, K, or S; X 4 is I, Q, E, or T; X 5 is S or K; X 6 is S or E; X 7 is W, S, N or E; X 8 is D or E; X 9 is N, T or R; X 10 is T or R; X 11 is F, D, K, S or H; X 12 is V or Q; X 13 is I or N.
  • the antibody includes a VRC01-like heavy chain variable domain as disclosed herein and a light chain variable domain, wherein the light chain variable domain includes the LCDR1, LCD2 and/or LCD3 of SEQ ID NO: 238, as defined using the Kabat or IMGT CDR positions, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the LCDR1, LCDR2 and LCDR3 of SEQ ID NO: 238, as defined using the Kabat or IMGT CDR positions, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a light chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the LCDR1, LCD2 and/or LCD3 of SEQ ID NO: 9, as defined using the Kabat or IMGT CDR positions, and further includes a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 9, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 9, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 9, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the HCDR1, HCD2 and/or HCD3 of SEQ ID NO: 2, as defined using the Kabat or IMGT CDR positions, and further includes an amino acid substitution at Kabat position F97 (such as a F97D, F97K, F97S, F97H), and further includes a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 2, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 2, a FR1 having at least 85%, at least 90%, at least 95%, at least 98%, at least 99% sequence identity with the FR1 (IMGT or Kabat) of SEQ ID NO: 2, a FR1 having at
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat).
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238 (Kabat).
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (IMGT).
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238 (IMGT).
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the light chain of the antibody includes the LCDR1, LCDR2, and/or LCD3 of SEQ ID NO: 238, and further includes an amino acid substitution at Kabat position F97, which is included in the LCDR3 of SEQ ID NO: 238 using either Kabat or IMGT positioning.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is F (VRC01 light chain Kabat CDRs with F97), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is D (VRC01 light chain Kabat CDRs with F97D), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is D (VRC01 light chain Kabat CDRs with F97D), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is K (VRC01 light chain Kabat CDRs with F97K), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is K (VRC01 light chain Kabat CDRs with F97K), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is S (VRC01 light chain Kabat CDRs with F97S), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is S (VRC01 light chain Kabat CDRs with F97S), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is H (VRC01 light chain Kabat CDRs with F97H), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is F (VRC01 light chain IMGT CDRs with F97), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is D (VRC01 light chain IMGT CDRs with F97D), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is K (VRC01 light chain IMGT CDRs with F97K), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is S (VRC01 light chain IMGT CDRs with F97S), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is H (VRC01 light chain IMGT CDRs with F97H), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is E; X 2 is I; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01 light chain; SEQ ID NO: 9).
  • the light chain can be complemented with any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is E; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01L V3E light chain; SEQ ID NO: 219).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is K; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01L V3K light chain; SEQ ID NO: 220).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01L V3S light chain; SEQ ID NO: 221).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 is D; X 9 is N; X 10 is T; X 11 is D; X 12 is V; X 13 is I (VRC01L F97D light chain; SEQ ID NO: 222).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 is D; X 9 is N; X 10 is T; X 11 is K; X 12 is V; X 13 is I (VRC01L F97K light chain; SEQ ID NO: 223).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 is D; X 9 is N; X 10 is T; X 11 is S; X 12 is V; X 13 is I (VRC01L F97S light chain; SEQ ID NO: 224).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is H; X 12 is V; X 13 is I (VRC01L F97H light chain; SEQ ID NO: 225).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is E; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 is D; X 9 is N; X 10 is T; X 11 is S; X 12 is V; X 13 is I (VRC01L V3E/F97S light chain; SEQ ID NO:226).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is E; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 is D; X 9 is N; X 10 is T; X 11 is H; X 12 is V; X 13 is I (VRC01L V3E/F97H light chain; SEQ ID NO: 227).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is E; X 2 is I; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is S; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01hpL03 light chain; SEQ ID NO: 228).
  • SEQ ID NO: 238 wherein X 1 is E; X 2 is I; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is S; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01hpL03 light chain; SEQ ID NO: 228).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is E; X 2 is I; X 3 is V; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01hpL04 light chain; SEQ ID NO: 229).
  • SEQ ID NO: 238 wherein X 1 is E; X 2 is I; X 3 is V; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01hpL04 light chain; SEQ ID NO: 229).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is E; X 2 is I; X 3 is V; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is Q; X 13 is N (VRC01hpL05 light chain; SEQ ID NO: 230).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is E; X 2 is I; X 3 is V; X 4 is E; X 5 is K; X 6 is E; X 7 is E; X 8 is E; X 9 is R; X 10 is R; X 11 is F; X 12 is Q; X 13 is N (VRC01hpL06 light chain; SEQ ID NO: 231).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is T; X 5 is S; X 6 is S; X 7 is S; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is Q; X 13 is N (VRC01hpL02 E1/I2 deletion/V3S light chain; SEQ ID NO: 232).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is I; X 5 is S; X 6 is S; X 7 is S; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01hpL03 E1/I2 deletion/V3S light chain; SEQ ID NO: 233).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01hpL04 E1/I2 deletion/V3S light chain; SEQ ID NO: 234).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is Q; X 13 is N (VRC01hpL05 E1/I2 deletion/V3S light chain; SEQ ID NO: 235).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is E; X 5 is K; X 6 is E; X 7 is E; X 8 is E; X 9 is R; X 10 is R; X 11 is F; X 12 is Q; X 13 is N (VRC01hpL06 E1/I2 deletion/V3S light chain; SEQ ID NO: 236).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is E; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01hpL04 E1/I2 deletion/V3E light chain; SEQ ID NO: 237).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01L E1/I2 deletion; SEQ ID NO: 53).
  • the light chain can be complemented with any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 238, wherein X 1 is E; X 2 is I; X 3 is S; X 4 is T; X 5 is S; X 6 is S; X 7 is S; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is Q; X 13 is N (VRC01hpL02; SEQ ID NO: 50).
  • the light chain can be complemented with VRC07 heavy chain or any of the VRC07 heavy chain variants disclosed herein (such as the antibody heavy chains described in the above section) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the light chain can be complemented with the heavy chain of a known VRC01-like antibody (for example the heavy chain of VRC01, NIH4546, or NIH4546 G54W) to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • an isolated VRC01-like monoclonal antibody is provided, wherein the antibody includes a VRC01-like heavy chain and a VRC01-like light chain, wherein the light chain further includes deletion of the first two amino acids of the light chain, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the deletion includes and E1, I2 deletion.
  • VRC01-like monoclonal antibody light chain variable domains that can be modified with the deletion of the first two amino acids of the light chain include the light chain variable domains of the VRC01, VRC02, VRC03, NIH4546, NIH4546 G54W, VRC-PG04, VRC-PG04b, VRC-CH30, VRC-CH31, VRC-CH32, VRC-CH33, VRC-CH34, 3BNC60, 3BNC117, 12A12, 12A21, 1NC9, 1B2530, 8ANC131 or 8ANC134 monoclonal antibodies.
  • the sequence of accession numbers of the heavy chain variable domains of these antibodies are familiar to the person of ordinary skill in the art and provided herein.
  • the disclosed heavy and light chain variable domains can be included on heavy and light chains and cross-complemented to generate a monoclonal antibody that specifically binds to gp120 and is neutralizing.
  • the disclosed antibodies have increased binding affinity for gp120 compared to VRC01, but are not self-reactive, and/or have low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), and the light chain variable domain of the antibody includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat).
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • the light chain variable domain of the antibody includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat).
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), and the light chain variable domain of the antibody includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238 (Kabat).
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • the light chain variable domain of the antibody includes amino acids 24-32 (CDR1), 48-54 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238 (Kabat).
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), and the light chain variable domain of the antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (IMGT).
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), and the light chain variable domain of the antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238 (IMGT).
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is G, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is F, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3 of SEQ ID NO: 40
  • X 2 is G
  • the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is F, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is G, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is D, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3 of SEQ ID NO: 40
  • X 2 is G
  • the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is D
  • the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is G, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is K, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3 of SEQ ID NO: 40
  • X 2 is G
  • the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is K, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is G, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is S, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3 of SEQ ID NO: 40
  • X 2 is G
  • the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is S, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is G, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is H, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is H, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is F, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3 of SEQ ID NO: 40
  • X 2 is H
  • the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is F, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is H, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is D, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3 of SEQ ID NO: 40
  • X 2 is H
  • the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is D
  • the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is H, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is K, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3 of SEQ ID NO: 40
  • X 2 is H
  • the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is K, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is H, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is S, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 CDR3 of SEQ ID NO: 40
  • X 2 is H
  • the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is S, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40 (IMGT), wherein X 2 is H, wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is H, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is S, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is F, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is G and X 3 is S
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is S, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is D, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is G and X 3 is S
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is S, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is K, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is G and X 3 is S
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is S, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is S, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is G and X 3 is S
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is S, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is H, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is S, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is F, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is H and X 3 is S
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is S, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is D, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is H and X 3 is S
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is S, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is K, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is H and X 3 is S
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is S, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is S, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is H and X 3 is S
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is S, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is H, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is N, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is F, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is G and X 3 is N
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is N, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is D, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is G and X 3 is N
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is N, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is K, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is G and X 3 is N
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is N, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is S, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is G and X 3 is N
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is G and X 3 is N, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is H, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is N, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is F, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is H and X 3 is N
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is N, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is D, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is H and X 3 is N
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is N, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is K, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is H and X 3 is N
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is N, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is S, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat)
  • X 2 is H and X 3 is N
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 40 (Kabat), wherein X 2 is H and X 3 is N, wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 238 (Kabat), wherein X 11 is H, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 196 (NIH4546 heavy chain variable domain, IMGT CDRs), further including a glycine to histidine substitution at Kabat position 54 (a G54H substitution), and wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 215 (IMGT), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 97-114
  • SEQ ID NO: 196 N-4546 heavy chain variable domain, IMGT CDRs
  • the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 196 (NIH4546 heavy chain variable domain, IMGT CDRs), further including a glycine to histidine substitution at Kabat position 54 (a G54H substitution), and wherein the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 215 (IMGT), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 97-114
  • SEQ ID NO: 196 N-4546 heavy chain variable domain, IMGT CDRs
  • the light chain variable domain includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 196 (NIH4546 heavy chain variable domain, Kabat CDRs), further including a glycine to histidine substitution at Kabat position 54 (a G54H substitution), and wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 215 (Kabat), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 31-35
  • CDR2 50-66
  • CDR3 99-114
  • SEQ ID NO: 196 N-4546 heavy chain variable domain, Kabat CDRs
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (C
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes amino acids 31-35 (CDR1), 50-66 (CDR2) and/or 99-114 (CDR3) of SEQ ID NO: 196 (NIH4546 heavy chain variable domain, Kabat CDRs), further including a glycine to histidine substitution at Kabat position 54 (a G54H substitution), and wherein the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 215 (Kabat), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • CDR1 amino acids 31-35
  • CDR2 50-66
  • CDR3 99-114
  • SEQ ID NO: 196 N-4546 heavy chain variable domain, Kabat CDRs
  • the light chain variable domain includes amino acids 24-32 (CDR1), 48-54 (CDR2) and/or 87-91 (C
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 196 (NIH4546 heavy chain variable domain), further including a glycine to histidine substitution at Kabat position 54 (a G54H substitution), and wherein the light chain variable domain includes the amino acid sequence set forth as SEQ ID NO: 215 (Kabat), wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain includes the amino acid sequence of SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is S and X 4 is T (VRC07 G54H; SEQ ID NO: 32) and wherein the light chain variable domain includes a light chain variable domain as described herein, or a known VRC01-like light chain variable domain.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain of the antibody includes SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is S and X 4 is T (VRC07 G54H; SEQ ID NO: 32), and the light chain of the antibody includes:
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain includes the amino acid sequence of SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is N and X 4 is T (VRC07 G54H, S58N), and wherein the light chain variable domain includes a light chain variable domain as described herein, or a known VRC01-like light chain variable domain.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain of the antibody includes SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is N and X 4 is T (VRC07 G54H, S58N; SEQ ID NO: 258), and the light chain of the antibody includes:
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain includes the amino acid sequence of SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is S and X 4 is A (VRC07 I37V, G54H, T93A; SEQ ID NO: 259), and wherein the light chain variable domain includes a light chain variable domain as described herein, or a known VRC01-like light chain variable domain.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain of the antibody includes SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is S and X 4 is A (VRC07 I37V, G54H, T93A; SEQ ID NO: 259), and the light chain of the antibody includes:
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain includes the amino acid sequence of SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is N and X 4 is A (VRC07 I37V, G54H, S58N, T93A; SEQ ID NO: 260), and wherein the light chain variable domain includes a light chain variable domain as described herein, or a known VRC01-like light chain variable domain.
  • the antibody is not self-reactive, and/or has low self-reactivity.
  • the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain of the antibody includes SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is N and X 4 is A (VRC07 I37V, G54H, S58N, T93A; SEQ ID NO: 260), and the light chain of the antibody includes:
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain includes the amino acid sequence of SEQ ID NO: 196 (NIH4546 heavy chain variable domain), further including a glycine to histidine substitution at Kabat position 54 (a G54H substitution), and wherein the light chain variable domain includes a light chain variable domain as described herein, or a known VRC01-like light chain variable domain.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the antibody includes a heavy chain variable domain and a light chain variable domain, wherein the antibody specifically binds gp120, and wherein the antibody is neutralizing, wherein the heavy chain variable domain of the antibody includes SEQ ID NO: 196 (NIH4546 heavy chain variable domain), further including a glycine to histidine substitution at Kabat position 54 (a G54H substitution), and the light chain of the antibody includes:
  • the isolated monoclonal antibody specifically binds gp120, and includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 1, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody specifically binds gp120, and includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 29, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 2, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 3 and wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 4 and wherein the antibody specifically binds gp120 wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 1, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody specifically binds gp120, and includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 29, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 2, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 3 and wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 4 and wherein the antibody specifically binds gp120 wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 30, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of one of SEQ ID NOs: 31-36, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 30, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of one of SEQ ID NOs: 31-36, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q; X 16 is V or I and X 17 is A or T.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q or R; X 16 is V and X 17 is A or T.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q or R; X 16 is V or I and X 17 is A.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q; X 16 is V and X 17 is A or T.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q or R; X 16 is V and X 17 is A.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q; X 16 is V or I and X 17 is A.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 39, wherein the antibody specifically binds gp120 of HIV-1.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q or R; X 16 is V and X 17 is A or T.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q or R; X 16 is V or I and X 17 is A.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q; X 16 is V and X 17 is A or T.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q or R; X 16 is V and X 17 is A.
  • the monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38, wherein X 15 is Q; X 16 is V or I and X 17 is A.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 39, wherein the antibody specifically binds gp120 of HIV-1.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 1 or SEQ ID NO: 29.
  • a heavy chain variable domain including an amino acid sequence set forth as SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 4.
  • the isolated monoclonal antibody specifically binds gp120, and includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 23, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 24, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 25 and wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 26 and wherein the antibody specifically binds gp120 wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 23, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 24, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 25 and wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 26 and wherein the antibody specifically binds gp120 wherein the antibody is neutralizing.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 23.
  • a heavy chain variable domain including an amino acid sequence set forth as SEQ ID NO: 24, SEQ ID NO: 25, or SEQ ID NO: 26.
  • the monoclonal antibody includes a heavy chain variable domain including the amino acid sequence set forth as SEQ ID NO: 30.
  • a heavy chain variable domain including an amino acid sequence set forth as SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35 or SEQ ID NO: 36.
  • the isolated monoclonal antibody includes a heavy chain variable domain including the amino acid sequence set forth as SEQ ID NO: 38.
  • the monoclonal antibody includes a heavy chain variable domain including the amino acid sequence set forth as SEQ ID NO: 38, wherein X 15 is Q; X 16 is V or I and X 17 is A or T.
  • the monoclonal antibody includes a heavy chain variable domain including the amino acid sequence set forth as SEQ ID NO: 38, wherein X 15 is Q or R; X 16 is V and X 17 is A or T.
  • the monoclonal antibody includes a heavy chain variable domain including the amino acid sequence set forth as SEQ ID NO: 38, wherein X 15 is Q or R; X 16 is V or I and X 17 is A.
  • the monoclonal antibody includes a heavy chain variable domain the amino acid sequence set forth as SEQ ID NO: 38, wherein X 15 is Q; X 16 is V and X 17 is A or T.
  • the monoclonal antibody includes a heavy chain variable domain including the amino acid sequence set forth as SEQ ID NO: 38, wherein X 15 is Q or R; X 16 is V and X 17 is A.
  • the monoclonal antibody includes a heavy chain variable domain including the amino acid sequence set forth as SEQ ID NO: 38, wherein X 15 is Q; X 16 is V or I and X 17 is A.
  • the isolated monoclonal antibody includes a heavy chain variable domain the amino acid sequence set forth as SEQ ID NO: 39.
  • the light chain of the isolated human monoclonal antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 6 wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the light chain of the isolated human monoclonal antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 7, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the light chain of the isolated human monoclonal antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 8, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the light chain of the isolated human monoclonal antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the light chain of the isolated human monoclonal antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the light chain of the isolated human monoclonal antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6 wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the light chain of the isolated human monoclonal antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7 wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the light chain of the isolated human monoclonal antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8 wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the light chain of the isolated human monoclonal antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9 wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the light chain of the isolated human monoclonal antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the monoclonal antibody includes a light chain variable domain including SEQ ID NO: 6.
  • specific, non-limiting examples are antibodies that include a light chain variable domain that includes an amino acid sequence set forth as SEQ ID NO: 7 or SEQ ID NO: 8.
  • the monoclonal antibody includes a light chain variable domain including SEQ ID NO: 9.
  • the monoclonal antibody includes a light chain variable domain including as SEQ ID NO: 27.
  • the light chain variable domain of the antibody includes amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 41.
  • the light chain variable domain of the antibody includes SEQ ID NO: 41, wherein X 1 is E, X 2 is I, X 3 is I, X 4 is W, X 5 is N, X 6 is V, and X 7 is I [VRC01].
  • the light chain variable domain includes SEQ ID NO: 41, wherein X 1 is no amino acid, X 2 is no amino acid, X 3 is I, X 4 is W, X 5 is N, X 6 is V, and X 7 is I [VRC01 E1/I2 deletion].
  • the light chain variable domain includes SEQ ID NO: 41, wherein X 1 is no amino acid, X 2 is no amino acid, X 3 is I, X 4 is W, X 5 is T, X 6 is V, and X 7 is I [VRC01 E1/I2 deletion N72T].
  • the light chain variable domain includes SEQ ID NO: 41, wherein X 1 is E, X 2 is I, X 3 is T, X 4 is 5, X 5 is T, X 6 is Q, and X 7 is N.
  • the light chain variable domain includes SEQ ID NO: 41, wherein X 1 is no amino acid, X 2 is no amino acid, X 3 is T, X 4 is 5, X 5 is T, X 6 is Q, and X 7 is N.
  • the antibody specifically binds gp120, and wherein the antibody is neutralizing
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 40, and a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 41, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is S and X 4 is T, and a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 41, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is N and X 4 is T, and a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 41, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • CDR1 amino acids 26-33
  • CDR2 51-58
  • CDR3 97-114
  • X 4 is T
  • a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 41 wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 40, and a light chain variable domain including SEQ ID NO: 41.
  • the heavy chain variable domain of the antibody includes one of: (a) SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is S and X 4 is T; (b) SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is N and X 4 is T; (c) SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is S and X 4 is A; or (d) SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is N and X 4 is A and the light chain variable domain includes SEQ ID NO: 41.
  • the heavy chain variable domain of the antibody includes one of: (a) SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is S and X 4 is T; (b) SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is N and X 4 is T; (c) SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is S and X 4 is A; or (d) SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is N and X 4 is V; and the light chain variable domain includes one of (e) SEQ ID NO: 41, wherein X 1 is E, X 2 is I, X 3 is I, X 4 is W, X 5 is N, X 6 is V, and X 7 is I [VRC01]; (f) SEQ ID NO: 41, wherein X 1 is no amino acid, X 2 is
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 1, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 6, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 2, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 3, and the light chain variable domain and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 7, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 4, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 8, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 1, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 2, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 3, and the light chain variable domain and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 4, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 1, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the heavy chain variable domain of the monoclonal antibody includes amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 3, and the light chain variable domain and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 4, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 30, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 6, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 30, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of one of SEQ ID NOs: 31-36, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 6, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of one of SEQ ID NOs: 31-36, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 30, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 7, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 30, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of one of SEQ ID NOs: 31-36, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 7, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of one of SEQ ID NOs: 31-36, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 30, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 8, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 30, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of one of SEQ ID NOs: 31-36, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 8, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of one of SEQ ID NOs: 31-36, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 30, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 30, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of one of SEQ ID NOs: 31-36, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of one of SEQ ID NOs: 31-36, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 30, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 30, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of one of SEQ ID NOs: 31-36, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of one of SEQ ID NOs: 31-36, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 30 and a light chain variable domain including SEQ ID NO: 6. In other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 30 and a light chain variable domain including SEQ ID NO: 7. In yet other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 30 and a light chain variable domain including SEQ ID NO: 8. In additional examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 30 and a light chain variable domain including SEQ ID NO: 9. In more examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 30 and a light chain variable domain including SEQ ID NO: 27.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 31 and a light chain variable domain including SEQ ID NO: 6. In other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 31 and a light chain variable domain including SEQ ID NO: 7. In yet other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 31 and a light chain variable domain including SEQ ID NO: 8. In additional examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 31 and a light chain variable domain including SEQ ID NO: 9. In more examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 31 and a light chain variable domain including SEQ ID NO: 27.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 32 and a light chain variable domain including SEQ ID NO: 6. In other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 32 and a light chain variable domain including SEQ ID NO: 7. In yet other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 32 and a light chain variable domain including SEQ ID NO: 8. In additional examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 32 and a light chain variable domain including SEQ ID NO: 9. In more examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 32 and a light chain variable domain including SEQ ID NO: 27.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 33 and a light chain variable domain including SEQ ID NO: 6. In other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 33 and a light chain variable domain including SEQ ID NO: 7. In yet other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 33 and a light chain variable domain including SEQ ID NO: 8. In additional examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 33 and a light chain variable domain including SEQ ID NO: 9. In more examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 33 and a light chain variable domain including SEQ ID NO: 27.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 34 and a light chain variable domain including SEQ ID NO: 6. In other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 34 and a light chain variable domain including SEQ ID NO: 7. In yet other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 34 and a light chain variable domain including SEQ ID NO: 8. In additional examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 34 and a light chain variable domain including SEQ ID NO: 9. In more examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 34 and a light chain variable domain including SEQ ID NO: 27.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 35 and a light chain variable domain including SEQ ID NO: 6. In other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 35 and a light chain variable domain including SEQ ID NO: 7. In yet other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 35 and a light chain variable domain including SEQ ID NO: 8. In additional examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 35 and a light chain variable domain including SEQ ID NO: 9. In more examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 35 and a light chain variable domain including SEQ ID NO: 27.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 36 and a light chain variable domain including SEQ ID NO: 6. In other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 36 and a light chain variable domain including SEQ ID NO: 7. In yet other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 36 and a light chain variable domain including SEQ ID NO: 8. In additional examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 36 and a light chain variable domain including SEQ ID NO: 9. In more examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 36 and a light chain variable domain including SEQ ID NO: 27.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38 or SEQ ID NO: 39, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 6, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38 or SEQ ID NO: 39, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38 or SEQ ID NO: 39, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 7, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38 or SEQ ID NO: 39, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38 or SEQ ID NO: 39, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 8, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38 or SEQ ID NO: 39, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38 or SEQ ID NO: 39, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38 or SEQ ID NO: 39, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 38 or SEQ ID NO: 39, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38 or SEQ ID NO: 39, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 and wherein the antibody is neutralizing.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 38 and a light chain variable domain including SEQ ID NO: 6. In other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 38 and a light chain variable domain including SEQ ID NO: 7. In yet other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 38 and a light chain variable domain including SEQ ID NO: 8. In additional examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 38 and a light chain variable domain including SEQ ID NO: 9. In more examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 38 and a light chain variable domain including SEQ ID NO: 27.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 39 and a light chain variable domain including SEQ ID NO: 6. In other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 39 and a light chain variable domain including SEQ ID NO: 7. In yet other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 39 and a light chain variable domain including SEQ ID NO: 8. In additional examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 39 and a light chain variable domain including SEQ ID NO: 9. In more examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 39 and a light chain variable domain including SEQ ID NO: 27.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 1 and a light chain variable domain including SEQ ID NO: 6. In other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 2 and a light chain variable domain including SEQ ID NO: 9. In yet other examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 3 and a light chain variable domain including SEQ ID NO: 7. In additional examples, examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 4 and a light chain variable domain including SEQ ID NO: 8.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 3 and a light chain variable domain including SEQ ID NO: 9. In additional examples, examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 4 and a light chain variable domain including SEQ ID NO: 9.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 23, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 24, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 25 and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 26, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 23, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 24, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 25 and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 26, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and/or 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 23, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 24, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 25 and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 26, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 23, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 24, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 25 and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the isolated monoclonal antibody includes a heavy chain variable domain including amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 26, and includes a light chain variable domain including amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 23 and a light chain variable domain including SEQ ID NO: 9. In some examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 24 and a light chain variable domain including SEQ ID NO: 9. In some examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 25 and a light chain variable domain including SEQ ID NO: 9. In some examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 26 and a light chain variable domain including SEQ ID NO: 9. In some examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 23 and a light chain variable domain including SEQ ID NO: 27.
  • the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 24 and a light chain variable domain including SEQ ID NO: 27. In some examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 25 and a light chain variable domain including SEQ ID NO: 27. In some examples, the monoclonal antibody includes a heavy chain variable domain including SEQ ID NO: 26 and a light chain variable domain including SEQ ID NO: 27.
  • the monoclonal antibody includes the HCDR1, HCDR2 and/or HCDR3 or the LCDR1, LCDR2 and/or LCDR3 of one of the monoclonal antibody heavy or light chains encoded by one of the nucleic acid molecules listed in Table 2 or Table 3.
  • the monoclonal antibody includes the HCDR1, HCDR2 and HCDR3 or the LCDR1, LCDR2 and LCDR3 of one of the monoclonal antibody heavy or light chains encoded by one of the nucleic acid molecules listed in Table 2 or Table 3.
  • the monoclonal antibody includes a heavy chain variable domain or a light chain variable domain of one of the heavy or light chains encoded by one of the nucleic acid molecules listed in Table 2 or Table 3. In further embodiments, the monoclonal antibody includes a heavy chain or a light chain of one of the heavy or light chains encoded by one of the nucleic acid molecules listed in Table 2 or Table 3.
  • the heavy chain of the antibody includes at least 1 (such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13) amino acid substitutions compared to the amino acid sequence set forth as SEQ ID NO: 5 (VRC01 heavy chain variable domain).
  • the light chain of the antibody includes at least 1 (such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13) amino acid substitutions compared to the amino acid sequence set forth as SEQ ID NO: 9 (VRC01 light chain variable domain).
  • the heavy chain of the antibody includes at least 1 (such as at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 13) amino acid substitutions compared to the amino acid sequence set forth as SEQ ID NO: 2 (VRC07 heavy chain variable domain).
  • the disclosed monoclonal antibodies have a high affinity for gp120, such as a K D of ⁇ 3 nM for the antigenic epitope of gp120.
  • the VRC07 or variants of VRC07 compete with CD4 for binding to gp120.
  • a set of structure coordinates for the antibody or portions thereof in complex with gp120 or a portion thereof is a relative set of points that define a shape in three dimensions.
  • an entirely different set of coordinates could define a similar or identical shape.
  • slight variations in the individual coordinates will have little effect on overall shape.
  • the variations in coordinates discussed above may be generated because of mathematical manipulations of the structure coordinates.
  • the antibody is not self-reactive, and/or has low self-reactivity. In additional embodiments, the antibody is not immunogenic and/or has low immunogenicity. In several embodiments, the disclosed monoclonal antibodies specifically bind to the CD4 binding site on gp120 with an affinity greater than that of VRC01, but are less immunogenic than VRC01 when administered to a subject. In additional embodiments, the disclosed monoclonal antibodies specifically bind to the CD4 binding site on gp120 with an affinity greater than that of VRC01, but are less self-reactive than VRC01.
  • a disclosed antibody that is not self-reactive, or has low self reactivity completes competes poorly with an equal molar or less amount of a control antibody that is known to bind to self antigens.
  • the antibody can elicit about 50% or less inhibition, such as about 40%, 30%, 20% or 10% inhibition, of control antibody binding to anti-nuclear antigen and/or to cardiolipin.
  • the antibody has a five-fold or less, such as about six-fold, seven-fold, eight fold, nine-fold, or ten-fold less affinity for cardiolipin and/or nuclear antigen as compared to a control, such as a standard value or the affinity of the control antibody to cardiolipin and/or nuclear antigen, respectively.
  • an LS mutation can be added to the FcRn receptor binding region of an antibody. This mutation has no effect on neutralization breadth or potency, but increases the half-life of the antibody by 2- to 3-fold in both humanized mice and non-human primates. Additional the LS mutation to a monoclonal antibody is known to the person of skill in the art (see, e.g., Zalevsky, et al., Nature Biotechnology, 28:157-159, 2010).
  • the monoclonal antibodies disclosed herein can be of any isotype.
  • the monoclonal antibody can be, for example, an IgM or an IgG antibody, such as IgG 1 or an IgG 2 .
  • the class of an antibody that specifically binds gp120 can be switched with another.
  • a nucleic acid molecule encoding V L or V H is isolated using methods well-known in the art, such that it does not include any nucleic acid sequences encoding the constant region of the light or heavy chain, respectively.
  • the nucleic acid molecule encoding V L or V H is then operatively linked to a nucleic acid sequence encoding a C L or C H from a different class of immunoglobulin molecule.
  • This can be achieved using a vector or nucleic acid molecule that includes a C L or C H chain, as known in the art.
  • an antibody that specifically binds gp120 that was originally IgM may be class switched to an IgG. Class switching can be used to convert one IgG subclass to another, such as from IgG 1 to IgG 2 .
  • the disclosed antibodies are oligomers of antibodies, such as dimers trimers, tetramers, pentamers, hexamers, septamers, octomers and so on. In some examples, the antibodies are pentamers. The antibodies can also be included in a bi-specific antibody.
  • Antibody fragments of the antibodies disclosed herein are provided, which include a heavy chain and light chain variable domain and specifically bind gp120. These antibody fragments retain the ability to selectively bind with the antigen and are “antigen-binding” fragments. These fragments include, but are not limited to:
  • Fab the fragment which contains a monovalent antigen-binding fragment of an antibody molecule, can be produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain;
  • Fab′ the fragment of an antibody molecule can be obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; two Fab′ fragments are obtained per antibody molecule;
  • (Fab′) 2 the fragment of the antibody that can be obtained by treating whole antibody with the enzyme pepsin without subsequent reduction;
  • F(ab′) 2 is a dimer of two Fab′ fragments held together by two disulfide bonds;
  • Fv a genetically engineered fragment containing the variable domain of the light chain and the variable domain of the heavy chain expressed as two chains
  • Single chain antibody (such as scFv), defined as a genetically engineered molecule containing the variable domain of the light chain, the variable domain of the heavy chain, linked by a suitable polypeptide linker as a genetically fused single chain molecule.
  • a dimer of a single chain antibody (scFV 2 ), defined as a dimer of a scFV. This has also been termed a “miniantibody.”
  • variable domain included in the antibody is the variable domain of m912.
  • the antibodies are Fv antibodies, which are typically about 25 kDa and contain a complete antigen-binding site with three CDRs per each heavy chain and each light chain.
  • the V H and the V L can be expressed from two individual nucleic acid constructs in a host cell.
  • the V H amino acid sequence includes the CDRs from one of SEQ ID NOs: 1-4, 23-26, 30-36, 38-40, 199-201, 203-207, 216-218, or 258-260.
  • the V L amino acid sequence includes the CDRs from SEQ ID NOs: 6-9 or 27, 41-44, 50-55, 209-215, or 219-257.
  • the V H amino acid sequence includes the amino acid sequence set forth as one of SEQ ID NOs: 1-4, 23-26, 30-36, 38-40, 199-201, 203-207, 216-218, or 258-260.
  • the V L amino acid sequence includes the amino acid sequence set forth as one of SEQ ID NOs: 6-9 or 27, 41-44, 50-55, 209-215, or 219-257.
  • the chains of the Fv antibody are typically held together by noncovalent interactions.
  • these chains tend to dissociate upon dilution, so methods have been developed to crosslink the chains through glutaraldehyde, intermolecular disulfides, or a peptide linker.
  • the Fv can be a disulfide stabilized Fv (dsFv), wherein the heavy chain variable domain and the light chain variable domain are chemically linked by disulfide bonds.
  • the Fv fragments include V H and V L chains connected by a peptide linker.
  • These single-chain antigen binding proteins are prepared by constructing a structural gene including DNA sequences encoding the V H and V L domains connected by an oligonucleotide. The structural gene is inserted into an expression vector, which is subsequently introduced into a host cell such as E. coli . The recombinant host cells synthesize a single polypeptide chain with a linker peptide bridging the two V domains.
  • Methods for producing scFvs are known in the art (see Whitlow et al., Methods: a Companion to Methods in Enzymology , Vol.
  • Dimers of a single chain antibody are also contemplated.
  • Antibody fragments can be prepared by proteolytic hydrolysis of the antibody or by expression in E. coli of DNA encoding the fragment.
  • Antibody fragments can be obtained by pepsin or papain digestion of whole antibodies by conventional methods.
  • antibody fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment denoted F(ab′) 2 .
  • This fragment can be further cleaved using a thiol reducing agent, and optionally a blocking group for the sulfhydryl groups resulting from cleavage of disulfide linkages, to produce 3.5S Fab′ monovalent fragments.
  • an enzymatic cleavage using pepsin produces two monovalent Fab′ fragments and an Fc fragment directly (see U.S. Pat. No. 4,036,945 and U.S. Pat. No. 4,331,647, and references contained therein; Nisonhoff et al., Arch. Biochem. Biophys. 89:230, 1960; Porter, Biochem. J. 73:119, 1959; Edelman et al., Methods in Enzymology, Vol. 1, page 422, Academic Press, 1967; and Coligan et al. at sections 2.8.1-2.8.10 and 2.10.1-2.10.4).
  • cleaving antibodies such as separation of heavy chains to form monovalent light-heavy chain fragments, further cleavage of fragments, or other enzymatic, chemical, or genetic techniques may also be used, so long as the fragments bind to the antigen that is recognized by the intact antibody.
  • conservative variants of the antibodies can be produced. Such conservative variants employed in antibody fragments, such as dsFv fragments or in scFv fragments, will retain critical amino acid residues necessary for correct folding and stabilizing between the V H and the V L regions, and will retain the charge characteristics of the residues in order to preserve the low pI and low toxicity of the molecules. Amino acid substitutions (such as at most one, at most two, at most three, at most four, or at most five amino acid substitutions) can be made in the V H and the V L regions to increase yield.
  • the V H sequence is SEQ ID NOs: 1-4, 23-26, 30-36, 38-40, 199-201, 203-207, 216-218, or 258-260.
  • the V L sequence is SEQ ID NOs: 6-9 or 27, 41-44, 50-55, 209-215, or 219-257.
  • Conservative amino acid substitution tables providing functionally similar amino acids are well known to one of ordinary skill in the art. The following six groups are examples of amino acids that are considered to be conservative substitutions for one another:
  • the antibodies or antibody fragments disclosed herein can be derivatized or linked to another molecule (such as another peptide or protein).
  • the antibody or portion thereof is derivatized such that the binding to gp120 is not affected adversely by the derivatization or labeling.
  • the antibody can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (for example, a bispecific antibody or a diabody), a detection agent, a pharmaceutical agent, and/or a protein or peptide that can mediate associate of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).
  • One type of derivatized antibody is produced by cross-linking two or more antibodies (of the same type or of different types, such as to create bispecific antibodies).
  • Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (such as m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (such as disuccinimidyl suberate).
  • Such linkers are available from Pierce Chemical Company (Rockford, Ill.).
  • An antibody that specifically binds gp120 can be labeled with a detectable moiety.
  • Useful detection agents include fluorescent compounds, including fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin, lanthanide phosphors and the like.
  • Bioluminescent markers are also of use, such as luciferase, Green fluorescent protein, Yellow fluorescent protein.
  • An antibody can also be labeled with enzymes that are useful for detection, such as horseradish peroxidase, ⁇ -galactosidase, luciferase, alkaline phosphatase, glucose oxidase and the like.
  • an antibody When an antibody is labeled with a detectable enzyme, it can be detected by adding additional reagents that the enzyme uses to produce a reaction product that can be discerned. For example, when the agent horseradish peroxidase is present the addition of hydrogen peroxide and diaminobenzidine leads to a colored reaction product, which is visually detectable.
  • An antibody may also be labeled with biotin, and detected through indirect measurement of avidin or streptavidin binding. It should be noted that the avidin itself can be labeled with an enzyme or a fluorescent label.
  • An antibody may be labeled with a magnetic agent, such as gadolinium.
  • Antibodies can also be labeled with lanthanides (such as europium and dysprosium), and manganese.
  • Paramagnetic particles such as superparamagnetic iron oxide are also of use as labels.
  • An antibody may also be labeled with a predetermined polypeptide epitopes recognized by a secondary reporter (such as leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags).
  • labels are attached by spacer arms of various lengths to reduce potential steric hindrance.
  • An antibody can also be labeled with a radiolabeled amino acid.
  • the radiolabel may be used for both diagnostic and therapeutic purposes.
  • Examples of labels for polypeptides include, but are not limited to, the following radioisotopes or radionucleotides: 3 H, 14 C, 15 N, 35 S, 90 Y, 99 Tc, 111 In, 125 I, 131 I.
  • An antibody can also be derivatized with a chemical group such as polyethylene glycol (PEG), a methyl or ethyl group, or a carbohydrate group. These groups may be useful to improve the biological characteristics of the antibody, such as to increase serum half-life or to increase tissue binding.
  • PEG polyethylene glycol
  • methyl or ethyl group a methyl or ethyl group
  • carbohydrate group a chemical group such as polyethylene glycol (PEG), a methyl or ethyl group, or a carbohydrate group.
  • radiolabels may be detected using photographic film or scintillation counters
  • fluorescent markers may be detected using a photodetector to detect emitted illumination
  • Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting the reaction product produced by the action of the enzyme on the substrate, and colorimetric labels are detected by simply visualizing the colored label.
  • Nucleic acid molecules also referred to as polynucleotides
  • encoding the polypeptides provided herein can readily be produced by one of skill in the art.
  • these nucleic acids can be produced using the amino acid sequences provided herein (such as the CDR sequences, heavy chain and light chain sequences), sequences available in the art (such as framework sequences), and the genetic code.
  • V H nucleic acid sequences are set forth as SEQ ID NOs: 10-13, 37, 57-101, 103, 105, 107-140, 145-156, 161-164, and 177-194, and include degenerate variants;
  • exemplary V L nucleic acid sequences are set forth as SEQ ID NOs: 14-16, 141-144, 157-160, and 165-176, and include degenerate variants thereof.
  • One of skill in the art can readily use the genetic code to construct a variety of functionally equivalent nucleic acids, such as nucleic acids which differ in sequence but which encode the same antibody sequence, or encode a conjugate or fusion protein including the V L and/or V H nucleic acid sequence.
  • Nucleic acid sequences encoding the antibodies that specifically bind gp120 can be prepared by any suitable method including, for example, cloning of appropriate sequences or by direct chemical synthesis by methods such as the phosphotriester method of Narang et al., Meth. Enzymol. 68:90-99, 1979; the phosphodiester method of Brown et al., Meth. Enzymol. 68:109-151, 1979; the diethylphosphoramidite method of Beaucage et al., Tetra. Lett. 22:1859-1862, 1981; the solid phase phosphoramidite triester method described by Beaucage & Caruthers, Tetra. Letts.
  • Exemplary nucleic acids can be prepared by cloning techniques. Examples of appropriate cloning and sequencing techniques, and instructions sufficient to direct persons of skill through many cloning exercises are found in Sambrook et al., supra, Berger and Kimmel (eds.), supra, and Ausubel, supra. Product information from manufacturers of biological reagents and experimental equipment also provide useful information. Such manufacturers include the SIGMATM Chemical Company (Saint Louis, Mo.), R&D SystemsTM (Minneapolis, Minn.), Pharmacia Amersham (Piscataway, N.J.), CLONTECHTM Laboratories, Inc.
  • Nucleic acids can also be prepared by amplification methods.
  • Amplification methods include polymerase chain reaction (PCR), the ligase chain reaction (LCR), the transcription-based amplification system (TAS), the self-sustained sequence replication system (3SR).
  • PCR polymerase chain reaction
  • LCR ligase chain reaction
  • TAS transcription-based amplification system
  • 3SR self-sustained sequence replication system
  • nucleic acids encoding any of the antibodies, V H and/or V L , disclosed herein (or fragment thereof) can be expressed in a recombinantly engineered cell such as bacteria, plant, yeast, insect and mammalian cells. These antibodies can be expressed as individual V H and/or V L chain, or can be expressed as a fusion protein. An immunoadhesin can also be expressed. Thus, in some examples, nucleic acids encoding a V H and V L , and immunoadhesin are provided. The nucleic acid sequences can optionally encode a leader sequence.
  • the V H - and V L -encoding DNA fragments are operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly 4 -Ser) 3 (SEQ ID NO: 48), such that the V H and V L sequences can be expressed as a contiguous single-chain protein, with the V L and V H domains joined by the flexible linker (see, e.g., Bird et al., Science 242:423-426, 1988; Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883, 1988; McCafferty et al., Nature 348:552-554, 1990).
  • a cleavage site can be included in a linker, such as a furin cleavage site.
  • the nucleic acid encoding the V H and/or the V L optionally can encode an Fc domain (immunoadhesin).
  • the Fc domain can be an IgA, IgM or IgG Fc domain.
  • the Fc domain can be an optimized Fc domain, as described in U.S. Published Patent Application No. 20100/093979, incorporated herein by reference.
  • the immunoadhesin is an IgG 1 Fc.
  • the single chain antibody may be monovalent, if only a single V H and V L are used, bivalent, if two V H and V L are used, or polyvalent, if more than two V H and V L are used.
  • Bispecific or polyvalent antibodies may be generated that bind specifically to gp120 and another antigen, such as, but not limited to gp41, or that bind two different gp120 epitopes.
  • the encoded V H and V L optionally can include a furin cleavage site between the V H and V L domains.
  • the host cell can be a gram positive bacteria including, but not limited to, Bacillus, Streptococcus, Streptomyces, Staphylococcus, Enterococcus, Lactobacillus, Lactococcus, Clostridium, Geobacillus , and Oceanobacillus .
  • Methods for expressing protein in gram positive bacteria, such as Lactobaccillus are well known in the art, see for example, U.S. Published Patent Application No. 20100/080774.
  • Expression vectors for lactobacillus are described, for example in U.S. Pat. No. 6,100,388, and U.S. Pat. No. 5,728,571. Leader sequences can be included for expression in Lactobacillus .
  • Gram negative bacteria include, but not limited to, E. coli, Pseudomonas, Salmonella, Campylobacter, Helicobacter, Flavobacterium, Fusobacterium, Ilyobacter, Neisseria , and Ureaplasma.
  • One or more DNA sequences encoding the antibody or fragment thereof can be expressed in vitro by DNA transfer into a suitable host cell.
  • the cell may be prokaryotic or eukaryotic.
  • the term also includes any progeny of the subject host cell. It is understood that all progeny may not be identical to the parental cell since there may be mutations that occur during replication. Methods of stable transfer, meaning that the foreign DNA is continuously maintained in the host, are known in the art. Hybridomas expressing the antibodies of interest are also encompassed by this disclosure.
  • nucleic acids encoding the isolated proteins described herein can be achieved by operably linking the DNA or cDNA to a promoter (which is either constitutive or inducible), followed by incorporation into an expression cassette.
  • the promoter can be any promoter of interest, including a cytomegalovirus promoter and a human T cell lymphotrophic virus promoter (HTLV)-1.
  • an enhancer such as a cytomegalovirus enhancer, is included in the construct.
  • the cassettes can be suitable for replication and integration in either prokaryotes or eukaryotes. Typical expression cassettes contain specific sequences useful for regulation of the expression of the DNA encoding the protein.
  • the expression cassettes can include appropriate promoters, enhancers, transcription and translation terminators, initiation sequences, a start codon (i.e., ATG) in front of a protein-encoding gene, splicing signal for introns, sequences for the maintenance of the correct reading frame of that gene to permit proper translation of mRNA, and stop codons.
  • the vector can encode a selectable marker, such as a marker encoding drug resistance (for example, ampicillin or tetracycline resistance).
  • expression cassettes which contain, at the minimum, a strong promoter to direct transcription, a ribosome binding site for translational initiation (internal ribosomal binding sequences), and a transcription/translation terminator.
  • a strong promoter to direct transcription e. coli
  • a ribosome binding site for translational initiation e. coli
  • a transcription/translation terminator e. coli
  • control sequences can include a promoter and/or an enhancer derived from, for example, an immunoglobulin gene, HTLV, SV40 or cytomegalovirus, and a polyadenylation sequence, and can further include splice donor and/or acceptor sequences (for example, CMV and/or HTLV splice acceptor and donor sequences).
  • the cassettes can be transferred into the chosen host cell by well-known methods such as transformation or electroporation for E. coli and calcium phosphate treatment, electroporation or lipofection for mammalian cells. Cells transformed by the cassettes can be selected by resistance to antibiotics conferred by genes contained in the cassettes, such as the amp, gpt, neo and hyg genes.
  • Eukaryotic cells can also be cotransformed with polynucleotide sequences encoding the antibody, labeled antibody, or functional fragment thereof, and a second foreign DNA molecule encoding a selectable phenotype, such as the herpes simplex thymidine kinase gene.
  • Another method is to use a eukaryotic viral vector, such as simian virus 40 (SV40) or bovine papilloma virus, to transiently infect or transform eukaryotic cells and express the protein (see for example, Eukaryotic Viral Vectors , Cold Spring Harbor Laboratory, Gluzman ed., 1982).
  • a eukaryotic viral vector such as simian virus 40 (SV40) or bovine papilloma virus
  • SV40 simian virus 40
  • bovine papilloma virus bovine papilloma virus
  • Modifications can be made to a nucleic acid encoding a polypeptide described herein without diminishing its biological activity. Some modifications can be made to facilitate the cloning, expression, or incorporation of the targeting molecule into a fusion protein. Such modifications are well known to those of skill in the art and include, for example, termination codons, a methionine added at the amino terminus to provide an initiation, site, additional amino acids placed on either terminus to create conveniently located restriction sites, or additional amino acids (such as poly His) to aid in purification steps.
  • the immunoconjugates, effector moieties, and antibodies of the present disclosure can also be constructed in whole or in part using standard peptide synthesis well known in the art.
  • the recombinant immunoconjugates, antibodies, and/or effector molecules can be purified according to standard procedures of the art, including ammonium sulfate precipitation, affinity columns, column chromatography, and the like (see, generally, R. Scopes, PROTEIN PURIFICATION, Springer-Verlag, N.Y., 1982).
  • the antibodies, immunoconjugates and effector molecules need not be 100% pure.
  • the polypeptides should be substantially free of endotoxin.
  • a reducing agent must be present to separate disulfide bonds.
  • An exemplary buffer with a reducing agent is: 0.1 M Tris pH 8, 6 M guanidine, 2 mM EDTA, 0.3 M DTE (dithioerythritol).
  • Reoxidation of the disulfide bonds can occur in the presence of low molecular weight thiol reagents in reduced and oxidized form, as described in Saxena et al., Biochemistry 9: 5015-5021, 1970, and especially as described by Buchner et al., supra.
  • Renaturation is typically accomplished by dilution (for example, 100-fold) of the denatured and reduced protein into refolding buffer.
  • An exemplary buffer is 0.1 M Tris, pH 8.0, 0.5 M L-arginine, 8 mM oxidized glutathione (GSSG), and 2 mM EDTA.
  • the heavy and light chain regions are separately solubilized and reduced and then combined in the refolding solution.
  • An exemplary yield is obtained when these two proteins are mixed in a molar ratio such that a 5-fold molar excess of one protein over the other is not exceeded.
  • Excess oxidized glutathione or other oxidizing low molecular weight compounds can be added to the refolding solution after the redox-shuffling is completed.
  • the antibodies, labeled antibodies and functional fragments thereof that are disclosed herein can also be constructed in whole or in part using standard peptide synthesis.
  • Solid phase synthesis of the polypeptides of less than about 50 amino acids in length can be accomplished by attaching the C-terminal amino acid of the sequence to an insoluble support followed by sequential addition of the remaining amino acids in the sequence. Techniques for solid phase synthesis are described by Barany & Merrifield, The Peptides: Analysis, Synthesis, Biology. Vol. 2: Special Methods in Peptide Synthesis, Part A . pp. 3-284; Merrifield et al., J. Am. Chem. Soc.
  • Proteins of greater length may be synthesized by condensation of the amino and carboxyl termini of shorter fragments. Methods of forming peptide bonds by activation of a carboxyl terminal end (such as by the use of the coupling reagent N,N′-dicylohexylcarbodimide) are well known in the art.
  • Methods are disclosed herein for the prevention or treatment of an HIV infection, such as an HIV-1 infection.
  • Prevention can include inhibition of infection with HIV-1.
  • the methods include contacting a cell with a therapeutically effective amount of the human monoclonal antibodies or antigen binding fragment thereof disclosed herein that specifically binds gp120, or an nucleic acid encoding such antibodies or antigen binding fragments.
  • the method can also include administering to a subject a therapeutically effective amount of the human monoclonal antibodies or antigen binding fragments to a subject, or an nucleic acid encoding such antibodies or antigen binding fragments thereof.
  • the antibodies, or an antigen binding fragment or an nucleic acid encoding such antibodies or antigen binding fragments can be used pre-exposure (for example, to prevent or inhibit HIV infection).
  • the antibodies, or an antigen binding fragment or an nucleic acid encoding such antibodies or antigen binding thereof can be used in post-exposure prophylaxis.
  • antibodies or antigen binding fragment or an nucleic acid encoding such antibodies or antigen binding fragment can be used to eliminate or reduce the viral reservoir of HIV in a subject.
  • a therapeutically effective amount of an antibody or antigen binding fragment or an nucleic acid encoding such antibodies or antibody binding fragments can be administered to a subject being treated with anti-viral therapy.
  • the antibodies, or an antibody binding fragment is modified such that it is directly cytotoxic to infected cells, or uses natural defenses such as complement, antibody dependent cellular cytotoxicity (ADCC), or phagocytosis by macrophages.
  • ADCC antibody dependent cellular cytotoxicity
  • Methods to assay for neutralization activity include, but are not limited to, a single-cycle infection assay as described in Martin et al. (2003) Nature Biotechnology 21:71-76.
  • the level of viral activity is measured via a selectable marker whose activity is reflective of the amount of viable virus in the sample, and the IC50 is determined.
  • acute infection can be monitored in the PM1 cell line or in primary cells (normal PBMC).
  • the level of viral activity can be monitored by determining the p24 concentrations using ELISA. See, for example, Martin et al. (2003) Nature Biotechnology 21:71-76.
  • a composition can decrease HIV infection by a desired amount, for example by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination of detectable HIV infected cells), as compared to HIV infection in the absence of the composition.
  • the cell is also contacted with a therapeutically effective amount of an additional agent, such as anti-viral agent.
  • the cell can be in vivo or in vitro.
  • the methods can include administration of one on more additional agents known in the art.
  • HIV replication can be reduced or inhibited by similar methods.
  • a composition can decrease HIV replication by a desired amount, for example by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination of detectable HIV), as compared to HIV replication in the absence of the composition.
  • the cell is also contacted with a therapeutically effective amount of an additional agent, such as anti-viral agent.
  • the cell can be in vivo or in vitro.
  • compositions include one or more of the antibodies that specifically bind gp120, or binding fragment thereof or a nucleic acid encoding such antibodies or antigen binding fragments, that are disclosed herein in a carrier.
  • the compositions can be prepared in unit dosage forms for administration to a subject. The amount and timing of administration are at the discretion of the treating physician to achieve the desired purposes.
  • the antibody can be formulated for systemic or local administration. In one example, the antibody that specifically binds gp120, or an antigen binding fragment thereof or a nucleic acid encoding such antibodies or antigen binding fragments, is formulated for parenteral administration, such as intravenous administration.
  • compositions for administration can include a solution of the antibody that specifically binds gp120, or an antigen binding fragment thereof or an nucleic acid encoding such antibodies or antibody binding fragments, dissolved in a pharmaceutically acceptable carrier, such as an aqueous carrier.
  • a pharmaceutically acceptable carrier such as an aqueous carrier.
  • aqueous carriers can be used, for example, buffered saline and the like. These solutions are sterile and generally free of undesirable matter.
  • These compositions may be sterilized by conventional, well known sterilization techniques.
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
  • concentration of antibody in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the subject's
  • a typical pharmaceutical composition for intravenous administration includes about 0.1 to 10 mg of antibody per subject per day. Dosages from 0.1 up to about 100 mg per subject per day may be used, particularly if the agent is administered to a secluded site and not into the circulatory or lymph system, such as into a body cavity or into a lumen of an organ. Actual methods for preparing administrable compositions will be known or apparent to those skilled in the art and are described in more detail in such publications as Remington's Pharmaceutical Science, 19th ed., Mack Publishing Company, Easton, Pa. (1995).
  • Antibodies, or an antigen binding fragment thereof or an nucleic acid encoding such an antibodies or antigen binding fragments may be provided in lyophilized form and rehydrated with sterile water before administration, although they are also provided in sterile solutions of known concentration.
  • the antibody solution, or an antigen binding fragment or an nucleic acid encoding such antibodies or antibody binding fragments is then added to an infusion bag containing 0.9% sodium chloride, USP, and typically administered at a dosage of from 0.5 to 15 mg/kg of body weight.
  • Antibodies, or an antigen binding fragment thereof or an nucleic acid encoding such antibodies or antigen binding fragments can be administered by slow infusion, rather than in an intravenous push or bolus.
  • a higher loading dose is administered, with subsequent, maintenance doses being administered at a lower level.
  • an initial loading dose of 4 mg/kg may be infused over a period of some 90 minutes, followed by weekly maintenance doses for 4-8 weeks of 2 mg/kg infused over a 30 minute period if the previous dose was well tolerated.
  • a therapeutically effective amount of a gp120-specific antibody, or an antigen binding fragment thereof or an nucleic acid encoding such antibodies or antibody binding fragments will depend upon the severity of the disease and/or infection and the general state of the patient's health.
  • a therapeutically effective amount of the antibody is that which provides either subjective relief of a symptom(s) or an objectively identifiable improvement as noted by the clinician or other qualified observer.
  • administration of the antibody, or antibody binding fragment or an nucleic acid encoding such antibodies or antibody binding fragments results in a reduction in the establishment of HIV infection and/or reducing subsequent HIV disease progression in a subject.
  • a reduction in the establishment of HIV infection and/or a reduction in subsequent HIV disease progression encompass any statistically significant reduction in HIV activity.
  • methods for treating a subject with an HIV-1 infection include administering to the subject a therapeutically effective amount of an antibody, or a nucleic acid encoding the antibody, thereby preventing or treating the HIV-1 infection.
  • a therapeutically effective amount of a human gp120-specific antibody or antigen binding fragment thereof or nucleic acid encoding such antibodies or antibody antigen binding fragments is administered in order to prevent transmission of HIV, or decrease the risk of transmission of HIV, from a mother to an infant.
  • a therapeutically effective amount of the antibody, or an antibody binding fragment or nucleic acid encoding such antibodies or antigen binding fragment is administered to mother and/or to the child at childbirth.
  • a therapeutically effective amount of the antibody, antigen binding fragment, or nucleic acid encoding the antibody or antigen binding fragment is administered to the mother and/or infant prior to breast feeding in order to prevent viral transmission to the infant or decrease the risk of viral transmission to the infant.
  • both a therapeutically effective amount of the antibody, antigen binding fragment, or nucleic acid encoding the antibody or antigen binding fragment and a therapeutically effective amount of another agent, such as zidovudine, is administered to the mother and/or infant.
  • the antibody, antigen binding fragment, or nucleic acid encoding the antibody or antigen binding fragment can be combined with anti-retroviral therapy.
  • Antiretroviral drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits.
  • nucleoside analog reverse-transcriptase inhibitors such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, entecavir, and apricitabine
  • nucleotide reverse transcriptase inhibitors such as tenofovir and adefovir
  • non-nucleoside reverse transcriptase inhibitors such as efavirenz, nevirapine, delavirdine, etravirine, and rilpivirine
  • protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, fosamprenavir, atazanavir, tipranavir, and darunavir
  • entry or fusion inhibitors such as maraviroc and enfuvirtide
  • a subject is further administered one or more additional antibodies that bind HIV glycoproteins, such as gp120 and gp41.
  • additional antibodies that bind HIV glycoproteins, such as gp120 and gp41.
  • neutralizing antibodies that can be administered in conjunction with the disclosed antibodies can be found in International Patent Publication No. WO 2011/038290, published Mar. 31, 2011, which is specifically incorporated herein by reference in its entirety.
  • compositions including the antibody, antigen binding fragment, or nucleic acid encoding the antibody or antigen binding fragment, that are disclosed herein, are administered depending on the dosage and frequency as required and tolerated by the patient.
  • the composition should provide a sufficient quantity of at least one of the antibodies disclosed herein to effectively treat the patient.
  • the dosage can be administered once, but may be applied periodically until either a therapeutic result is achieved or until side effects warrant discontinuation of therapy.
  • a dose of the antibody is infused for thirty minutes every other day.
  • about one to about ten doses can be administered, such as three or six doses can be administered every other day.
  • a continuous infusion is administered for about five to about ten days.
  • the subject can be treated at regular intervals, such as monthly, until a desired therapeutic result is achieved.
  • the dose is sufficient to treat or ameliorate symptoms or signs of disease without producing unacceptable toxicity to the patient.
  • Controlled-release parenteral formulations can be made as implants, oily injections, or as particulate systems.
  • Particulate systems include microspheres, microparticles, microcapsules, nanocapsules, nanospheres, and nanoparticles.
  • Microcapsules contain the therapeutic protein, such as a cytotoxin or a drug, as a central core. In microspheres the therapeutic is dispersed throughout the particle.
  • Particles, microspheres, and microcapsules smaller than about 1 ⁇ m are generally referred to as nanoparticles, nanospheres, and nanocapsules, respectively.
  • Capillaries have a diameter of approximately 5 ⁇ m so that only nanoparticles are administered intravenously.
  • Microparticles are typically around 100 ⁇ m in diameter and are administered subcutaneously or intramuscularly. See, for example, Kreuter, J., Colloidal Drug Delivery Systems , J. Kreuter, ed., Marcel Dekker, Inc., New York, N.Y., pp. 219-342 (1994); and Tice & Tabibi, Treatise on Controlled Drug Delivery , A. Kydonieus, ed., Marcel Dekker, Inc. New York, N.Y., pp. 315-339, (1992).
  • Polymers can be used for ion-controlled release of the antibody compositions disclosed herein.
  • Various degradable and nondegradable polymeric matrices for use in controlled drug delivery are known in the art (Langer, Accounts Chem. Res. 26:537-542, 1993).
  • the block copolymer, polaxamer 407 exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel at body temperature. It has been shown to be an effective vehicle for formulation and sustained delivery of recombinant interleukin-2 and urease (Johnston et al., Pharm. Res. 9:425-434, 1992; and Pec et al., J. Parent. Sci. Tech. 44(2):58-65, 1990).
  • hydroxyapatite has been used as a microcarrier for controlled release of proteins (Ijntema et al., Int. J. Pharm. 112:215-224, 1994).
  • liposomes are used for controlled release as well as drug targeting of the lipid-capsulated drug (Betageri et al., Liposome Drug Delivery Systems , Technomic Publishing Co., Inc., Lancaster, Pa. (1993)).
  • Numerous additional systems for controlled delivery of therapeutic proteins are known (see U.S. Pat. No. 5,055,303; U.S. Pat. No. 5,188,837; U.S. Pat. No. 4,235,871; U.S. Pat. No. 4,501,728; U.S. Pat. No.
  • a subject is administered the DNA encoding the antibody or antigen binding fragments thereof, or one or more of the CDRs grafted onto a protein scaffold, to provide in vivo antibody production, for example using the cellular machinery of the subject.
  • Immunization by nucleic acid constructs is well known in the art and taught, for example, in U.S. Pat. No. 5,643,578, and U.S. Pat. No. 5,593,972 and U.S. Pat. No. 5,817,637.
  • U.S. Pat. No. 5,880,103 describes several methods of delivery of nucleic acids encoding to an organism. The methods include liposomal delivery of the nucleic acids. Such methods can be applied to the production of an antibody, or antibody binding fragments thereof, by one of ordinary skill in the art.
  • nucleic acids are direct administration with plasmid DNA, such as with a mammalian expression plasmid.
  • plasmid DNA such as with a mammalian expression plasmid.
  • the nucleotide sequence encoding the disclosed antibody, or antibody binding fragments thereof, can be placed under the control of a promoter to increase expression.
  • a disclosed antibody, or antibody binding fragments thereof can also be expressed by attenuated viral hosts or vectors or bacterial vectors.
  • Recombinant vaccinia virus, adeno-associated virus (AAV), herpes virus, retrovirus, cytomegalovirus or other viral vectors can be used to express the antibody.
  • vaccinia vectors and methods useful protocols are described in U.S. Pat. No. 4,722,848.
  • BCG Bacillus Calmette Guerin provides another vector for expression of the disclosed antibodies (see Stover, Nature 351:456-460, 1991).
  • a nucleic acid encoding a disclosed antibody, or antibody binding fragments thereof is introduced directly into cells.
  • the nucleic acid can be loaded onto gold microspheres by standard methods and introduced into the skin by a device such as Bio-Rad's HELIOSTM Gene Gun.
  • the nucleic acids can be “naked,” consisting of plasmids under control of a strong promoter.
  • the DNA is injected into muscle, although it can also be injected directly into other sites.
  • Dosages for injection are usually around 0.5 ⁇ g/kg to about 50 mg/kg, and typically are about 0.005 mg/kg to about 5 mg/kg (see, e.g., U.S. Pat. No. 5,589,466).
  • a method is provided herein for the detection of the expression of gp120 in vitro or in vivo.
  • expression of gp120 is detected in a biological sample, and can be used to detect HIV-1 infection as the presence of HIV-1 in a sample.
  • the sample can be any sample, including, but not limited to, tissue from biopsies, autopsies and pathology specimens.
  • Biological samples also include sections of tissues, for example, frozen sections taken for histological purposes.
  • Biological samples further include body fluids, such as blood, serum, plasma, sputum, spinal fluid or urine.
  • a method for detecting AIDS and/or an HIV-1 infection in a subject provides a method for detecting HIV-1 in a biological sample, wherein the method includes contacting a biological sample with the antibody under conditions conducive to the formation of an immune complex, and detecting the immune complex, to detect the gp120 in the biological sample.
  • the detection of gp120 in the sample indicates that the subject has an HIV infection.
  • the detection of gp120 in the sample indicates that the subject has AIDS.
  • detection of gp120 in the sample confirms a diagnosis of AIDS and/or an HIV-1 infection in a subject.
  • the disclosed antibodies are used to test vaccines. For example to test if a vaccine composition assumes the same conformation as a gp120 peptide.
  • a method for testing a vaccine wherein the method includes contacting a sample containing the vaccine, such as a gp120 immunogen, with the antibody under conditions conducive to the formation of an immune complex, and detecting the immune complex, to detect the vaccine in the sample.
  • the detection of the immune complex in the sample indicates that vaccine component, such as such as a gp120 immunogen assumes a conformation capable of binding the antibody.
  • the antibody is directly labeled with a detectable label.
  • the antibody that binds gp120 (the first antibody) is unlabeled and a second antibody or other molecule that can bind the antibody that binds gp120 is utilized.
  • a second antibody is chosen that is able to specifically bind the specific species and class of the first antibody.
  • the first antibody is a human IgG
  • the secondary antibody may be an anti-human-IgG.
  • Other molecules that can bind to antibodies include, without limitation, Protein A and Protein G, both of which are available commercially.
  • Suitable labels for the antibody or secondary antibody include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, magnetic agents and radioactive materials.
  • suitable enzymes include horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase.
  • suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin.
  • suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin.
  • a non-limiting exemplary luminescent material is luminol; a non-limiting exemplary a magnetic agent is gadolinium, and non-limiting exemplary radioactive labels include 125 I, 131 I, 35 S or 3 H.
  • Kits for detecting a polypeptide will typically include an antibody that binds gp120, such as any of the antibodies disclosed herein.
  • an antibody fragment such as an Fv fragment or a Fab is included in the kit.
  • the antibody is labeled (for example, with a fluorescent, radioactive, or an enzymatic label).
  • kits in one embodiment, includes instructional materials disclosing means of use.
  • the instructional materials may be written, in an electronic form (such as a computer diskette or compact disk) or may be visual (such as video files).
  • the kits may also include additional components to facilitate the particular application for which the kit is designed.
  • the kit may additionally contain means of detecting a label (such as enzyme substrates for enzymatic labels, filter sets to detect fluorescent labels, appropriate secondary labels such as a secondary antibody, or the like).
  • the kits may additionally include buffers and other reagents routinely used for the practice of a particular method. Such kits and appropriate contents are well known to those of skill in the art.
  • the diagnostic kit includes an immunoassay.
  • the method of detecting gp120 in a biological sample generally includes the steps of contacting the biological sample with an antibody which specifically reacts, under immunologically reactive conditions, to gp120.
  • the antibody is allowed to specifically bind under immunologically reactive conditions to form an immune complex, and the presence of the immune complex (bound antibody) is detected directly or indirectly.
  • An isolated monoclonal antibody comprising a heavy chain variable domain and a light chain variable domain, wherein a heavy chain variable domain of the antibody comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 1, and wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • An isolated monoclonal antibody comprising a heavy chain variable domain and a light chain variable domain, wherein a heavy chain variable domain of the antibody comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 23, and wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • Clause 23 The isolated monoclonal antibody of any one of clauses 1-18, wherein the light chain variable domain of the antibody comprises SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 27.
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 1
  • the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 2 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO:3 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7; or
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 4 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8.
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 23 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 24 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 25 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 26 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 23 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 24 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 25 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27; or
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 26 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27.
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 30, and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 30 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO:30 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 30 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 30 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 31, and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 31 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 31 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 31 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 31 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 32
  • the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 32 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO:32 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 32 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 32 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 33
  • the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 33 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO:33 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 33 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 33 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 34
  • the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 34 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO:34 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 34 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 34 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 35
  • the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 35 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO:35 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 35 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 35 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 36
  • the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 36 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO:36 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 36 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8; or
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 37 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27.
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38
  • the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO:38 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 38 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 39
  • the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 6;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 39 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 9;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 39 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 7;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 39 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 8;
  • the heavy chain variable domain comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 39 and the light chain variable domain comprises amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 27;
  • An isolated monoclonal antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain of the antibody comprises amino acids 26-33 (CDR1), 51-58 (CDR2) and/or 97-114 (CDR3) of SEQ ID NO: 40, wherein the antibody specifically binds gp120 of HIV-1, and wherein the antibody is neutralizing.
  • Clause 40 The isolated antigen binding fragment of clause 39, wherein the fragment is a Fab fragment, a Fab′ fragment, a F(ab)′ 2 fragment, a single chain Fv protein (scFv), or a disulfide stabilized Fv protein (dsFv).
  • the fragment is a Fab fragment, a Fab′ fragment, a F(ab)′ 2 fragment, a single chain Fv protein (scFv), or a disulfide stabilized Fv protein (dsFv).
  • Clause 41 The isolated antigen binding fragment of clause 40, wherein the antigen binding fragment is a Fab or an scFv fragment.
  • Clause 42 The isolated monoclonal antibody of any of clauses 1-41, or an antigen binding fragment thereof, wherein the antibody or antigen binding fragment is labeled.
  • Clause 43 The isolated monoclonal antibody or antigen binding fragment of clause 42, wherein the label is a fluorescent, enzymatic, or radioactive label.
  • Clause 44 A composition comprising a therapeutically effective amount of the antibody of clauses 1-38, or an antigen binding fragment thereof, and a pharmaceutically acceptable carrier.

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